Cardiovascular Risk in Philadelphia-Negative Myeloproliferative Neoplasms: Mechanisms and Implications-A Narrative Review.

Myeloproliferative neoplasms (MPNs), encompassing disorders like polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are characterized by clonal hematopoiesis without the Philadelphia chromosome. The JAK2 V617F mutation is prevalent in PV, ET, and PMF, while mutations in MPL and CALR also play significant roles. These conditions predispose patients to thrombotic events, with PMF exhibiting the lowest survival among MPNs. Chronic inflammation, driven by cytokine release from aberrant leukocytes and platelets, amplifies cardiovascular risk through various mechanisms, including atherosclerosis and vascular remodeling. Additionally, MPN-related complications like pulmonary hypertension and cardiac fibrosis contribute to cardiovascular morbidity and mortality. This review consolidates recent research on MPNs' cardiovascular implications, emphasizing thrombotic risk, chronic inflammation, and vascular stiffness. Understanding these associations is crucial for developing targeted therapies and improving outcomes in MPN patients.

Diagnostic Values of Serum Inflammatory Biomarkers after Hip and Knee Arthroplasty in Patients with Periprosthetic Joint Infection.

One of the complications after total hip arthroplasty (THA) or total knee arthroplasty (TKA) is periprosthetic joint infection (PJI). Numerous studies have been performed to explore the value of biological parameters in the early identification of infection rates after THA and TKA. This study investigates alterations in inflammatory markers associated with PJI. This retrospective study focused on a cohort of patients with hip and knee arthroplasty treated between 2016 and 2022. CRP, ESR, and fibrinogen were observed preoperatively, on days one, three, six, and twenty-one postoperatively. From a total of 4076 THA and TKA performed during this period, 62 patients were identified with periprosthetic infections. We also identified the pathogens responsible for infections in order to assess if asymptomatic preoperative infections were involved in PJI. In patients with acute infections following TKA, days one and three postoperative recorded a CRP value below the expected range. The value of CRP in patients with early infection after THA was significantly increased on day six postoperative. ESR and fibrinogen values were not statistically significantly correlated with early PJI. The CRP level in acute PJI shows different patterns than those shown in the literature.

The Impact of Anemia on the Survival of Patients Diagnosed With Low-Grade Malignant B-cell Lymphomas.

INTRODUCTION: B-cell lymphomas with a low degree of malignancy represent a heterogeneous group of diseases, that evolve slowly, but present particularities in terms of long-term survival. METHODS: We investigated the impact of anemia from the time of diagnosis in 249 patients with malignant B-cell lymphomas, diagnosed between January 2011 and December 2015, in the Hematology Department of the Sibiu County Emergency Hospital, Romania. RESULTS: We included 126 (50.6%) male and 123 (49.4%) female patients with the average age being 68.2 years. Among all patients, 106 (42.6%) were diagnosed with chronic lymphocytic leukemia (CLL), 61 (24.5%) with marginal zone lymphoma (MZL), 53 (21.3%) with multiple myeloma (MM), 16 (6.4%) with follicular lymphoma (FL), nine (3.6%) with plasmacytoma, and four cases with hairy cell leukemia (HCL). The serum Hb value in the subject group varied between 2.6 g/dL and 17 g/dL. At diagnosis, 18 (7.2%) patients had severe anemia, 32 (12.9%) had moderate anemia, 58 (23.3%) had mild anemia, and 141 (56.6%) had no anemia at all at the time of diagnosis. In our group, the higher degree of anemia was correlated with a more advanced stage of the disease but not with the older age of the patients. Our study's highest median value of LDH corresponded to moderate anemia and the lowest value to patients who did not have anemia. Patients who did not have anemia at diagnosis had the best survival at five years, followed by those with mild anemia, then those with moderate anemia. CONCLUSION: In our cohort, subjects with the lowest Hb value at diagnosis had the worst survival. The results of our study conclude that anemia represents a negative impact factor not only on the patient's quality of life but also on their survival.

Incidence of Subclinical Deep Vein Thrombosis after Total Hip and Knee Arthroplasty Is Not Correlated with Number of Tranexamic Acid Doses.

Background: Recent studies increasingly highlight the efficacy of tranexamic acid administration in total hip arthroplasty (THA) and total knee arthroplasty (TKA). However, the optimal dosage of tranexamic acid is still controversial. Methods: The current study analyzes the efficiency of tranexamic acid dosage and the number of administrations in THA and TKA. The objective of this study is to compare the incidence of deep vein thrombosis (DVT) based on the number of dosages. We divided the patients into two groups; one group received a single dosage, and the other group received two dosages. Doppler ultrasound examinations were conducted on the lower limbs of all patients at both six and thirty days postoperatively. The second objective is to compare the decrease in hemoglobin (Hb) in the two groups. Results: The results show that there is no difference in DVT incidence between the patients with different TXA numbers of dosages. There is no statistically significant decrease in Hb between the two groups at day one and day five postoperatively. Day one shows a statistically higher average in the two-dose group, approximately 0.06 g/dL, and day five shows a slightly elevated average in the single-dose group, approximately 0.06 g/dL. Blood transfusion requirements show no significant differences in the groups; one patient in the single-dose tranexamic acid group needed transfusion at day five postoperatively, while two patients in each group required immediate postoperative transfusion. Conclusion: There was no increase in the incidence of deep vein thrombosis among patients receiving two dosages of tranexamic acid.

IL-1 Beta-A Biomarker for Ischemic Stroke Prognosis and Atherosclerotic Lesions of the Internal Carotid Artery.

Background and Objectives: Stroke is a leading cause of mortality and morbidity worldwide. Treatment of this pathology is still under development and its risk factors remain to be determined. Therefore, we aim to determine the role of interleukin-1 beta in atherosclerotic lesions of the internal carotid artery as a risk factor for stroke and the role of this biomarker in stroke prognosis. Materials and Methods: This study enrolled 56 patients diagnosed with ischemic stroke in the anterior vascular territory (AVT) and posterior vascular territory (PVT). All the patients had venous blood collected at admission and 7 days after the onset of the cerebral ischemia in order to determine the plasma concentration of interleukin-1 beta. At the same time, an extracranial carotid ultrasound was performed. Results: The interleukin-1 beta collected at admission was positively correlated with the NIHSS at admission (Pearson index 0.424), and both measurements were correlated with carotid stenosis (Spearmen correlation index of 0.529 and 0.653, respectively). Conclusions: Interleukin-1 beta could be a reliable biomarker for stroke prognosis and the development of atherosclerotic lesions of the internal carotid.

A Severity Score and Outcome Prediction in Patients that Suffered an Ischemic Stroke.

Background: Stroke is the main cause of disability and exitus worldwide. The prediction of mortality of this pathology represents a major challenge. More than that, the infection with the SARS-CoV-2 virus is a challenge for every clinician worldwide, and hypercoagulability is one of its biggest concerns that can lead to stroke. Objective: Our aim was to develop a severity stroke index for both SARS-CoV-2 stroke patients and noninfected stroke patients which we hope to be helpful in patient's management. Methods: We conducted a prospective study during January 2021-June 2021 which included 80 patients who suffered an ischemic stroke, 40 of which had both stroke and SARS-CoV-2 infection. We have established a panel of biomarkers including CRP, IL-6, fibrinogen, ESR, D-dimer, leucocytes, lymphocytes, and NLR and compared the results of our two cohorts. Results: SARS-CoV-2 stroke patients have experienced elevated levels of biomarkers that rise in inflammation such as hs-CRP, IL-6, and D-dimer, comparing to noninfected stroke patients. Also, the probability of exitus in SARS-CoV-2 patients is 4.2 times higher than in noninfected subjects. With regard to stroke severity, we have concluded that a NIHSS score higher than 15 points considerably influences the death rate, the probability of exitus being 9.16 times higher than in NIHSS score lower than 15. Conclusion: Based on our result, we have established a severity score index which includes NIHSS score, age, gender, the presence/absence of COVID-19 infection, and the following biomarkers: hs-PCR, IL-6, D-dimer, fibrinogen, and ESR, which can be used as a tool to guide patient's management.

Prognostic markers for ischemic stroke - are they truly reliable?

Background: Stroke is one of the leading causes of mortality and morbidity worldwide. Despite extensive research, to this date there is no panel of biomarkers for the prevention and prognosis of ischemic stroke and there is still much incomplete and insufficiently researched information. Aim: We conducted a prospective, observational study between January and June 2020. The main objective of this study was to clarify the role of inflammation markers, i.e. neutrophil/ lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), high-sensitivity C - reactive protein (hsCRP) in ischemic stroke and whether there is or not a correlation between these markers and carotid stenosis. Study design: In the study we included 150 subjects divided in two groups: study group - 100 subjects and control group - 50 subjects. Methods: Data collected during the research (at the time of patient admission): 1) biological sample: 5 ml of peripheral blood were collected in a vial with clot activator and separating gel, from which the following laboratory tests were performed: hsCRP, neutrophils, lymphocytes, platelets. NLR and PLR were subsequently calculated as the ratio of neutrophils to lymphocytes, respectively platelets and lymphocytes), 2) paraclinical examinations: extracranial carotid Doppler ultrasound examination. Results: The results were impressive: high-sensitivity C reactive protein (hsCRP), neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) were strongly, respectively moderately correlated with the severity of stroke (the severity being established with the NIHS (National Institute of Health Stroke) score. None of the inflammation markers included in the present study was correlated with carotid stenosis. Conclusion: hsCRP, NLR and PLR may potentially be prognostic markers for ischemic stroke, being of major help in preventing its possible complications.

From a bispecific monoclonal antibody to gene therapy: A new era in the treatment of hemophilia A.

The treatment of hemophilia A has progressed amazingly in recent years. Emicizumab, a bispecific-humanized monoclonal antibody, is able to improve coagulation by bridging activated factor IX and factor X. Emicizumab is administered subcutaneously and much less often compared to factor VIII products. It has low immunogenicity, does not require dose adjustment, and can be administered regardless of the presence of factor VIII inhibitors. Thrombin generation assays but not factor VIII activity are indicated to guide and monitor the treatment. Emicizumab has enabled the conversion of patients with severe forms into patients with milder forms of hemophilia A. It has reduced the number of bleeding episodes compared to both on-demand and prophylactic substitution therapy and has an excellent safety profile. Gene therapy can elevate factor VIII plasma levels for many years after a single treatment course, could offer long-term protection from bleeding episodes, and minimize or eliminate the need for substitutive treatment with factor VIII concentrates. Gene therapy can provoke an immune response, manifested by an increase in common liver enzymes, that require immunotherapy. Long term monitoring is necessary to identify possible adverse effects. Future objectives are: the development of an ideal viral vector, the possibility of its re-administration, the use of gene therapy in hemophiliac children, and determining whether it can be successfully used to induce immune tolerance to factor VIII ceteri paribus. The future will determine the place of each type of treatment and group of patients for which it is indicated.

Role of biological markers and CT severity score in predicting mortality in patients with COVID­19: An observational retrospective study.

COVID-19 pandemic is a continuing ongoing emergency of public concern. Early identification of markers associated with disease severity and mortality can lead to a prompter therapeutic approach. The present study conducted a multivariate analysis of different markers associated with mortality in order to establish their predictive role. Confirmed cases of 697 patients were examined. Demographic data, clinical symptoms and comorbidities were evaluated. Laboratory and imaging severity scores were reviewed. A total of 133 (19.1%) out of 697 patients succumbed during hospitalization. Obesity was the most common comorbidity, followed by hypertension, diabetes, coronary heart disease and chronic kidney disease. Compared with the survivor patients, non-survivors had a higher prevalence of diabetes, chronic kidney disease and coronary heart disease, as well as higher values of laboratory markers such as neutrophil-lymphocyte ratio (NLR), D-dimer, procalcitonin, IL-6 and C Reactive protein (CRP) and respectively high values of imaging severity scores. Multivariate regression analysis showed that high values of the proposed markers and chest computerized tomography (CT) severity imaging score were predictive for in hospital death: NLR [hazard ratio (HR): 3.127 confidence interval (CI) 95: 2.137-4.576]; D-dimer [HR: 6.223 (CI 95:3.809-10.167)]; procalcitonin [HR: 4.414 (CI 95:2.804-6.948)]; IL-6 [HR: 3.344 (CI 95:1.423-7.855)]; CRP [HR:2.997 (CI 95:1.940-4.630)]; and CT severity score [HR: 3.068 (CI 95:1.777-5.299)]. Laboratory markers and imaging severity scores could be used to stratify mortality risk in COVID-19 patients.

Warfarin involvement, in comparison to NOACs, in the development of systemic atherosclerosis.

Adverse effects of drugs are one of the objective criteria used for choosing the most appropriate anticoagulant. It is worrying that warfarin may be involved in the progression of systemic atherosclerosis, as more and more articles suggest. Warfarin has been widely used in the past and has greater efficacy compared to dabigatran in patients with mechanical heart valves; there is an antidote to it and it is cheap. Unfortunately, warfarin inhibits the synthesis and activity of Matrix-Gla-Protein, which is the major vitamin K-dependent inhibitor of arterial calcification - an active process associated with atherosclerosis, stimulated by inflammatory mechanisms. Vitamin K antagonizes the NF-κB signaling mechanism and contributes to the prevention of arterial calcifications. Warfarin given in experimental animal models of atherosclerosis contributed to the occurrence of an increased number of aortic calcifications. Warfarin treatment used in clinical trials was associated with the progressive increase of coronary atheroma calcification. Younger patients are more sensitive to warfarin-related arterial calcifications compared to older patients, due to warfarin-induced cellular senescence changes. Non-vitamin K antagonist direct oral anticoagulants do not interact with vitamin K. Edoxaban reduces the inflammatory process in the vascular walls and the proliferation of smooth vascular muscle cells, so it is involved in the prevention of vascular maladaptive remodeling process. Apixaban is able to stabilize the coronary atherosclerotic process. Randomized clinical trials are needed to evaluate the impact of warfarin on plaque stability and cardiovascular evolution of patients.

The high-performance technology CRISPR/Cas9 improves knowledge and management of acute myeloid leukemia.

Knowledge on acute myeloid leukemia pathogenesis and treatment has progressed recently, but not enough to provide ideal management. Improving the prognosis of acute myeloid leukemia patients depends on advances in molecular biology for the detection of new therapeutic targets and the production of effective drugs. The CRISPR/Cas9 technology allows gene insertions and deletions and it is the first step in investigating the function of their encoded proteins. Thus, new experimental models have been developed and progress has been made in understanding protein metabolism, antitumor activity, leukemic cell maintenance, differentiation, growth, apoptosis, and self-renewal, the combined pathogenetic mechanisms involved in leukemogenesis. The CRISPR/Cas9 system is used to understand drug resistance and find solutions to overcome it. The therapeutic progress achieved using the CRISPR/Cas9 system is remarkable. FST gene removal inhibited acute myeloid leukemia cell growth. Lysine acetyltransferase gene deletion contributed to decreased proliferation rate, increased apoptosis, and favored differentiation of acute myelid leukemia cells carrying MLL-X gene fusions. The removal of CD38 gene from NK cells decreased NK fratricidal cells contributing to increased efficacy of new CD38 CAR-NK cells to target leukemic blasts. BCL2 knockout has synergistic effects with FLT3 inhibitors. Exportin 1 knockout is synergistic with midostaurin treatment in acute myeloid leukemia with FLT3-ITD mutation. Using the results of CRISPR/Cas9 libraries and technology application will allow us to get closer to achieving the goal of curing acute myeloid leukemia in the coming decades.

Management of patients with chronic lymphocytic leukemia during the SARS-CoV-2 pandemic.

Oncohematological patients are prone to develop infections due to immunosuppression caused by the disease and chemo-immunotherapy. The aim of this review was to outline the details of the management of patients with chronic lymphocytic leukemia (CLL) during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Patients with CLL often exhibit inadequate humoral and cellular immune responses to various infections and vaccinations. Patients under the 'watch and wait' strategy have a lower risk of infections, including with SARS-CoV-2, compared with those undergoing therapeutic interventions, but they still have a higher risk than age-matched controls. Patients with CLL have a high risk of developing severe forms of coronavirus disease-2019 (COVID-19), particularly if they are undergoing chemo-immunotherapy. The total anti-SARS-CoV-2 antibody titer demonstrates a slower increase in patients with CLL infected with the virus, and the antibody levels tend to decrease after reaching a maximum level sooner than in healthy individuals. This leads to a late negativation of the PCR tests and a longer duration of hospitalization. In total, ~1/3 of patients with CLL do not develop a persistent titer of antiviral antibodies, and this is associated with the presence of hypogammaglobulinemia. It appears that patients with CLL have the worst outcomes amongst patients with malignant hemopathies and SARS-CoV-2 infection. Bruton tyrosine kinase inhibitors reduce the hyperinflammatory status of patients with CLL with COVID-19, which is accompanied by decreased levels of serum inflammatory markers, ferritin and D-dimer, and serum levels of pro-inflammatory cytokines, but they increase the risk of infections and impaired humoral immunity. An abrupt discontinuation of these may promote the rapid decompensation of CLL, which may even mimic the clinical manifestations of COVID-I9, including a significant increase in cytokine release. In conclusion, therapeutic decisions must be personalized to each patient with CLL and each at risk patient must be quarantined during the SARS-CoV-2 pandemic to reduce their risk of contraction.

Thrombin Generation in Chronic Liver Diseases-A Pilot Study.

The knowledge about coagulation disorders in patients with chronic liver disease changed in the last decade. The aim of this study was to analyze the parameters of thrombin generation in patients with chronic liver disease, as they are the most appropriate biomarkers to explore coagulation. (1) Background: The knowledge about coagulation disorders in patients with chronic liver disease changed in the last decade. The study of thrombin generation in patients with chronic liver disease provides a much more accurate assessment of the coagulation cascade; (2) Methods: This study is a prospective observational pilot study on hospitalized patients with chronic liver diseases that analyzed thrombin generation performed from their platelet-poor plasma versus that of control subjects. We analyzed a group of 59 patients with chronic liver disease and 62 control subjects; (3) Results: Thrombin generation was lower in hepatitis and cirrhosis patients compared to controls and decreases as the disease progressed. Lag time was higher in ethanolic etiology compared to the control group. Peak thrombin and endogenous thrombin potential were shorter in all etiologies when compared to the control group. The velocity index was significantly lower in HCV hepatopathies, ethanolic, and mixed etiology when compared with normal individuals; (4) Conclusions: Given the variability of thrombin generation in patients with chronic liver disease, its assay could serve to identify patients with high thrombotic and hemorrhagic risk and establish personalized conduct toward them.

Coagulation disorders in SARS-CoV-2 infection.

A better understanding of the pathogenetic mechanisms triggered by SARS-CoV-2 infection may contribute to a more effective management of patients with COVID-19. Coagulation dysfunction is a key pathogenetic element of this disease as well as a challenge for practitioners. Marked inflammatory process found in severe forms of COVID-19, the complement activation, the cytokine storm, and disruption of the renin-angiotensin-aldosterone system are involved in the onset of thrombotic microangiopathy and large vessel coagulopathy. Virus-induced procoagulant activity occurs at the systemic level. Intravascular microthrombi disrupt vascularization in various tissues and organs, contributing to the occurrence of multiorgan failure and explain the higher morbidity and all-cause mortality of patients. It is estimated that almost 20% of patients with COVID-19 have significant coagulation disorders, and about a quarter of those hospitalized in intensive care units are prone to develop thrombosis events under prophylactic anticoagulant treatment. Some of patients who have been immunized after healing from the SARS-CoV-2 infection have a hypercoagulable state and are prone to develop thrombosis. Hypercoagulability is supported by thrombelastographic analysis: patients have an acceleration of the propagation phase of blood clot formation and higher clot strength. Markers of coagulation dysfunction in SARS-CoV2 are: decreased platelet count, increased INR, presence of fibrin degradation products, and especially higher plasma levels of D-dimers, which predict unfavorable outcome in these patients. Age, pre-existing diseases and associated risk factors, together with careful monitoring of clinical evolution and laboratory parameters allow the choice of the best personalized prophylactic or curative anticoagulant treatment.

Pragmatic Analysis of Dyslipidemia Involvement in Coronary Artery Disease: A Narrative Review.

BACKGROUND: Dyslipidemia is the main factor involved in the occurrence and progression of coronary artery disease. OBJECTIVE: The research strategy is aimed at analyzing new data on the pathophysiology of dyslipidemia involvement in coronary artery disease, the modalities of atherogenic risk estimation and therapeutic advances. METHODS: Scientific articles published in PubMed from January 2017 to February 2018 were searched using the terms "dyslipidemia" and "ischemic heart disease". RESULTS: PCSK9 contributes to the increase in serum levels of low-density lipoprotein-cholesterol and lipoprotein (a). The inflammation is involved in the progression of hyperlipidemia and atherosclerosis. Hypercholesterolemia changes the global cardiac gene expression profile and is thus involved in the increase of oxidative stress, mitochondrial dysfunction, and apoptosis initiated by inflammation. Coronary artery calcifications may estimate the risk of coronary events. The cardioankle vascular index evaluates the arterial stiffness and correlates with subclinical coronary atherosclerosis. The carotid plaque score is superior to carotid intima-media thickness for risk stratification in patients with familial hypercholesterolemia and both can independently predict coronary artery disease. The lipoprotein (a) and familial hypercholesterolemia have a synergistic role in predicting the risk of early onset and severity of coronary atherosclerosis. A decrease in atherosclerotic coronary plaque progression can be achieved in patients with plasma LDL-cholesterol levels below 70 mg/dL. A highly durable RNA interference therapeutic inhibitor of PCSK9 synthesis could be a future solution. CONCLUSION: The prophylaxis and treatment of coronary artery disease in a dyslipidemic patient should be based on a careful assessment of cardio-vascular risk factors and individual metabolic particularities, so it may be personalized.

Liver infarction in a patient with Clostridium Difficile colitis. A possible connection?

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Liver stiffness in chronic hepatitis C virus infection.

INTRODUCTION: The severity of liver fibrosis can be assessed noninvasively today by liver stiffness measurements. Vibration-controlled transient elastography, shear wave elastography or magnetic resonance elastography are techniques increasingly used for this purpose. METHODS: This article presents the recent advances in the use of new techniques for liver fibrosis assessment in chronic hepatitis C: the correlation between liver stiffness values and liver fibrosis estimated by liver biopsies, the prognosis role of liver stiffness values, their usefulness in monitoring the treatment response, in assessing the severity of portal hypertension and in estimating the presence of esophageal varices. Scientific articles from January 2017 to January 2018 were searched in PubMed and PubMed Central databases, using the terms "liver stiffness" and "hepatitis C". RESULTS: The median liver stiffness values measured with different techniques are not identical, so that FibroScan thresholds cannot be used on any other elastographic machine. The higher the liver's stiffness measurement, the higher the liver-related events in patients with chronic hepatitis C. A liver stiffness measurement over 17 kPa could be an independent predictor for the presence of esophageal varices as well as a spleen with a longitudinal span ≥ 15 cm for patients with a value of liver stiffness < 17 kPa. A progressive and persistent decrease in liver stiffness is dependent on sustained virological response achievement. The lack of liver stiffness decrease has been associated with relapsers and a low value of liver stiffness at baseline. CONCLUSION: Liver stiffness provides clues about the severity and evolution of liver disease.

The role of thrombin in central nervous system activity and stroke.

BACKGROUND: Thrombin is a key factor of hemostasis, mediating the conversion of fibrinogen into fibrin. Along with prothrombin, of which thrombin is the active derivative, it has been found locally expressed in the central nervous system. This article aims to describe the role of thrombin in the normal functioning of the central nervous system and stroke. METHODS: In this mini-review, the specialized databases Medscape, PubMed, and Web of Science, from the years 2003-2018, were used to find relevant documents by using MeSH terms: "thrombin" and "stroke". RESULTS: Prothrombin and thrombin influence neural development, protection and regeneration, thrombin being a relatively strong regulating factor of brain function. However, high levels of thrombin are detrimental to neuronal health, and cause atherosclerotic plaque development and instability - a leading cause of cerebral infarction. In stroke, thrombin promotes direct cellular toxicity, vascular disruption, oxidative stress and inflammatory response. There is a direct correlation between thrombin activity in the affected brain hemisphere and the infarction volume. Direct acting thrombin inhibitors, like dabigatran, significantly decrease the risk of ischemic stroke. CONCLUSION: Further studies on the correlation between thrombin levels, generation and activity and the risk and recurrence of ischemic cerebral stroke should give new insight on this association, resulting in an optimized practical therapeutic approach.

The inhibitors - a challenge for the management of patients with hereditary haemophilia A.

INTRODUCTION: Our research strategy was aimed at evaluating the possible implication of the type of factor VIII product administered as substitution treatment to haemophilia A patients in the occurrence of inhibitors and their consequences on the management. METHODS: Scientific articles from July 2015 to July 2017 were searched using the PubMed and PubMed Central databases. The used search terms included "haemophilia A", "inhibitors", "plasma-derived factor VIII" and "recombinant factor VIII". RESULTS: The risk factors for inhibitors occurrence may be patients-related (genetic and nongenetic) and treatment-related. The possibility of a correlation between the increased purity of factor VIII given as substitution treatment and the occurrence of inhibitors is discussed in the light of literature data. Plasma-derived factor VIII is less immunogenic, but not entirely safe from the point of view of the possibility of transmitting biological agents. It is obvious that there is not enough plasma-derived factor VIII for the planet's needs. Recombinant factor VIII products have revolutionized the treatment of patients with haemophilia A over the past 3 decades by the disappearance of transfusion-related infections and their complications. They are safer in terms of pathogens and the new long-acting factor VIII products are based on recombinant DNA technology. CONCLUSION: Plasma-derived or recombinant factor VIII products must co-exist on the market for the benefit of haemophilic patients. Future solutions could be: less immunogenic factor VIII products, nonfactor replacement strategies, or bispecific antibody that mimics the function of coagulation factor VIII.

Thrombin generation - a potentially useful biomarker of thrombotic risk in Philadelphia-negative myeloproliferative neoplasms.

The diagnosis of essential thrombocythemia and polycythemia vera is often made during a thrombotic event which can be serious. Philadelphia-negative chronic myeloproliferative neoplasia patients have an increased thrombotic risk. This is assessed using various scoring systems but these are far from ideal and individual risk. The currend trend to personalised medicine requires finding the most useful thrombotic risk biomarker in these patients. Routine tests for coagulation do not take account of both pro- and anti-coagulant factors which is why these tests are not useful in patients with Philadelphia-negative myeloproliferative neoplasms. Thrombin generation reflects more accurately the balance between pro- and anti-coagulant factors. Some parameters of thrombin generation such as the endogenous thrombin potential are higher in Philadelphia-negative myeloproliferative neoplasm patients, especially in JAK2 V617F carriers than in healthy controls. They are even higher in those with reactive thrombocytosis. The JAK2 V617F allele burden correlates more with a higher thrombin generation potential in patients who are not treated with hydroxycarbamidum. Instead, JAK2 V617F-positive patients with Philadelphia-negative myeloproliferative neoplasms were the most sensitive to hydroxycarbamidum, as was reflected in lower values of platelet thrombin generation potential. The use of thrombin generation examination in these patients would enable detection of imminent thrombosis and personalised prophylactic management.