Chronic myeloid leukemia, tyrosine kinase inhibitors and cardiovascular system.

OBJECTIVE: Cardiovascular system health becomes important with the extended survival of chronic myeloid leukemia (CML) patients. Cardiotoxicities are related to the second- and third-generation tyrosine kinase inhibitors (TKIs). The most frequent and important cardiovascular events are myocardial infarction, stroke and peripheral arterial disease, QT prolongation, pleural effusions, and both systemic and pulmonary hypertension. The aim of this paper is to review the interactions between administrated TKIs and the cardiovascular system during the clinical course of CML. Elucidation of TKI effects on the cardiovascular system is vital since the current goal of CML therapy is a cure that leads to normal age and gender-similar survival with a normal quality of life. MATERIALS AND METHODS: Up to August 2022, literature searches were performed via the internet search engines MEDLINE, EMBASE, GOOGLE SCHOLAR: (i) chronic myeloid leukemia; (ii) tyrosine kinase inhibitor; (iii) cardiovascular system. Only articles in English and research including humans were included in the search. RESULTS: Tailored TKI treatment with individual patient characteristics must account for CML disease risk, patient age, patient comorbidities, patient compliance, TKI drug off-target risk profile, accelerated or blastic phase CML disease, pregnancy and allografting in CML. The treatment-free survival, improving quality of life, limiting adverse events of TKIs, and the optimal dose and administration duration of TKIs are still a matter of controversy. Special attention should be paid to the comorbidities of CML patients and clinical TKI effects on CVS since the aim of CML treatment is a cure that leads to normal age and gender-similar survival with a "normal" quality of life. CVS is an important morbidity and mortality cause for adult patients. The discontinuation of TKI treatment in CML and the treatment-free remission of CML patients are very important in order to reduce the risk for cardiovascular adverse effects of TKIs. The frail CML patients and especially the patients who have cardiac comorbidities, should be carefully evaluated for TKI treatment, and hematopoietic stem cell transplantation (HSCT) should be the last choice in these risky CML patients. CONCLUSIONS: The current CML treatment target is a cure that leads to normal age and gender-adjusted survival with a "normal" quality of life. Cardiovascular disorders are one of the major obstacles to reaching this target in CML patients. The treatment choices for CML patients must include a cardiovascular perspective.

Hematological aspects of the COVID-19 syndrome.

OBJECTIVE: Viral infections could complicate hematopoiesis and, in some cases, they may worsen the clinical prognosis of blood disorders. SARS-CoV-2 and COVID-19, as a viral disease, can have serious impact on the disease course of hematological neoplastic diseases and can cause hematological complications. The aim of this paper is to review the hematologic aspects of COVID-19 syndrome and the potential management options for SARS-CoV-2 including the convalescent plasma, hemostatic agents and proper anticoagulant treatment. MATERIALS AND METHODS: Up to February 2022, literature searches were performed using the internet search engines MEDLINE and EMBASE: (i) COVID-19; (ii) Hematology. PRISMA flow diagram described the COVID-19 and hematology search. RESULTS: According to our COVID-19 and hematology research on research databases, we included 82 studies in the current paper. The issues of the impact of the COVID-19 pandemic on hematological diseases, the role of t-lymphocytes in donor lymphocyte infusion and viruses, hemato-immunologic research in COVID-19, local bone marrow renin-angiotensin system and viral infections, clinical management of COVID-19 infection via hemostatic agents, immune plasma treatment of COVID-19, anticoagulant treatment of COVID-19 associated thrombosis are comprehensively described in this paper. CONCLUSIONS: The final episode of this pandemic will include the "chimerism-mediated immunotherapy" that will eventually lead to end of the COVID-19 process. The recent Omicron variant seems to have unique evasion effects on the interferon gene expression which will boost the chimerism-mediated immunotherapy without high mortality rates.

Clinical variations between three different causes of thrombocytopenia.

BACKGROUND: Thrombocytopenia is defined as the platelet count of less than 150 × 109/L and is a prominent cause of bleeding. Aplastic anemia (AA), immune thrombocytopenic purpura (ITP), and thrombotic thrombocytopenic purpura (TTP) are some of the reasons of low platelet counts. AIMS: We aimed to interpret different laboratory and clinical findings in these different reasons of thrombocytopenia. METHODS: Among patients with these disorders we assessed the performance of the ITP Bleeding Scale Assessment (ITP-BSA), which is principally designed for ITP patients. RESULTS: A hundred patients were included in analysis. Median platelet count at presentation was similar in all three groups. Thrombosis was seen more common in patients with TTP (20.7%) than the others (ITP; 5.6%, AA; 2.9%). In patients with TTP, sepsis (41.4%) and neurological findings (89.7%) are also more common than in the patients with ITP or AA. Bleeding was determined in all patients with AA. However, 13 patients with ITP (%36.1) and 10 patients with TTP (%34.5) had no bleeding. The most common bleeding site was skin in all three groups. There was not any gastrointestinal, lung, genitourinary, and cranial bleeding in patients with ITP. Patients with AA obtained the highest scores from the ITP-BSA. There was a significant difference between AA and the other two groups. The scores were found similar in patients with ITP and TTP (P = 0.17). CONCLUSION: Clinical variations in thrombocytopenic patients may vary and assist to diagnose the cause of thrombocytopenia. The bleeding scoring systems might be helpful.

Tailored tyrosine kinase inhibitor (TKI) treatment of chronic myeloid leukemia (CML) based on current evidence.

Philadelphia (Ph*)/BCR-ABL1-positive chronic myeloid leukemia (CML) is a neoplastic hematologic disorder, which is a functionally curable chronic disease via using tyrosine kinase inhibitor (TKI) drugs. The life expectancy for the vast majority of chronic phase-CML patients is "normal", thanks to the unique effectiveness of the ABL-targeted TKIs of CML. The patients with CML receiving TKI could be expected to have a survival and 'quality of life' of the age- and sex-matched healthy people. Several TKI pathways may be selected for the first line CML treatment, including first-generation original/generic imatinib or second-generation TKIs, such as bosutinib, nilotinib, and dasatinib. Individual characteristics of the CML patients, TKI drug compliance, lifestyle preferences, comorbidities, distinct toxicity profile of the TKI drug, and physician-clinical center experience are among the critical factors to be taken into account while deciding on the proper first line TKI in the newly diagnosed CML patients. Identifying CML patients at a higher risk for the disease progression or TKI resistance is essential and could influence the choice of primary TKI. The optimized integrations of the best available evidence, individual patient characteristics, and physician clinical experience are required in order to select best TKI for the CML management. Pathobiological basis depending upon the prospective in vivo research data is also crucial during the follow-up as well.

Three critical clinicobiological phases of the human SARS-associated coronavirus infections.

OBJECTIVE: COVID-19 immune syndrome is a multi-systemic disorder induced by the COVID-19 infection. Pathobiological transitions and clinical stages of the COVID-19 syndrome following the attack of SARS-CoV-2 on the human body have not been fully explored. The aim of this review is to outline the three critical prominent phase regarding the clinicogenomics course of the COVID-19 immune syndrome. MATERIALS AND METHODS: In the clinical setting, the COVID-19 process presents as "asymptomatic/pre-symptomatic phase", "respiratory phase with mild/moderate/severe symptoms" and "multi-systemic clinical syndrome with impaired/disproportionate and/or defective immunity". The corresponding three genomic phases include the "ACE2, ANPEP transcripts in the initial phase", "EGFR and IGF2R transcripts in the propagating phase" and the "immune system related critical gene involvements of the complicating phase". RESULTS: The separation of the phases is important since the genomic features of each phase are different from each other and these different mechanisms lead to distinct clinical multi-systemic features. Comprehensive genomic profiling with next generation sequencing may play an important role in defining and clarifying these three unique separate phases for COVID-19. From our point of view, it is important to understand these unique phases of the syndrome in order to approach a COVID-19 patient bedside. CONCLUSIONS: This three-phase approach may be useful for future studies which will focus on the clinical management and development of the vaccines and/or specific drugs targeting the COVID-19 processes. ANPEP gene pathway may have a potential for the vaccine development. Regarding the specific disease treatments, MAS agonists, TXA127, Angiotensin (1-7) and soluble ACE2 could have therapeutic potential for the COVID-19 course. Moreover, future CRISPR technology can be utilized for the genomic editing and future management of the clinical course of the syndrome.

Predictive factors for stem cell mobilization failure in multiple myeloma patients: A single center experience.

BACKGROUND AND AIM: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has been considered the standard of treatment care for patients with multiple myeloma (MM). Insufficient mobilization and harvest of peripheral stem cells can be a major obstacle for performing ASCT. This is resulting in a lacking opportunity of cure in patients with MM. The aim of this study was to evaluate the factors which influence mobilization failure in patients with MM. MATERIALS AND METHODS: This study has been performed in a retrospective manner. Two hundred and thirty-four patients with diagnosed MM who underwent stem cell mobilization after induction chemotherapy at Hacettepe University Hospital between the years of 2003 and 2018 were evaluated. RESULTS: A total of 234 patients were included in this study. The median age was 54 (32-76) years at the time of diagnosis. In 209 of 234 patients (89.3%) first mobilization trial was successful. At univariate analysis, among parameters identifiable before mobilization, male gender (p = 0.03), number of chemotherapy cycle before stem cell mobilization (p < 0.001), second ASCT (p < 0.001) and immunomodulatory treatment before stem cell mobilization (p < 0.001) predicted mobilization failure. At multivariate analysis, number of chemotherapy cycle before stem cell mobilization (p = 0.03), second ASCT (p < 0.001) and immunomodulatory treatment before stem cell mobilization (p = 0.02) retained independent predictive power. CONCLUSION: Detectable different clinical characteristics of MM patients before initiating mobilization may be predictors of poor mobilization. Therefore, the mobilization protocol should be evaluated on a patient basis. Minimization of exposure to chemotheraputic agents in MM patients, especially immunomodulatory agents, may increase CD34+ cell harvest yields.

Local bone marrow renin-angiotensin system in the genesis of leukemia and other malignancies.

The existence of a local renin-angiotensin system (RAS) specific to the hematopoietic bone marrow (BM) microenvironment had been proposed two decades ago. Most of the RAS molecules including ACE, ACE2, AGT, AGTR1, AGTR2, AKR1C4, AKR1D1, ANPEP, ATP6AP2, CMA1, CPA3, CTSA, CTSD, CTSG, CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP21A2, DPP3, EGFR, ENPEP, GPER, HSD11B1, HSD11B2, IGF2R, KLK1, LNPEP, MAS1, MME, NR3C1, NR3C2, PREP, REN, RNPEP, and THOP1 are locally present in the BM microenvironment. Local BM RAS peptides control the hematopoietic niche, myelopoiesis, erythropoiesis, thrombopoiesis and the development of other cellular lineages. Local BM RAS is important in hematopoietic stem cell biology and microenvironment. Angiotensin II regulates the proliferation, differentiation, and engraftment of hematopoietic stem cells. Activation of Mas receptor or ACE2 promotes proliferation of CD34+ cells. BM contains a progenitor that expresses renin throughout development. Angiotensin II attenuates the migration and proliferation of CD34+ Cells and promotes the adhesion of both MNCs and CD34+ cells. Renin cells in hematopoietic organs are precursor B cells. The renin cell requires RBP-J to differentiate. Mutant renin-expressing hematopoietic precursors can cause leukemia. Deletion of RBP-J in the renin-expressing progenitors enriches the precursor B-cell gene programme. Mutant cells undergo a neoplastic transformation, and mice develop a highly penetrant B-cell leukemia with multi-organ infiltration and early death. Many biological conditions during the development and function of blood cells are mediated by RAS, such as apoptosis, cellular proliferation, intracellular signaling, mobilization, angiogenesis, and fibrosis. The aim of this paper is to review recent developments regarding the actions of local BM RAS in the genesis of leukemia and other malignancies molecules.

MPV may reflect subcinical platelet activation in diabetic patients with and without diabetic retinopathy.

PURPOSE: To search subclinical platelet activation via detecting three important platelet activation parameters; mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT) in diabetic retinopathy (DR) in comparison with those in healthy adults as controls. METHODS: This prospective study included 140 patients who were followed-up at the Ankara Ulucanlar Eye Education and Research Hospital, and 40 normal subjects. All patients and control subjects underwent complete ophthalmologic evaluation. Of patients with type 2 diabetes, 43 cases with diabetes mellitus (DM) have no DR (Group 1), 45 cases with DM have nonproliferative DR (NPDR) (Group 2), and 52 cases with DM have proliferative DR (PDR) (Group 3). In addition, 40 age- and sex-matched healthy controls (Group 4) were included into the study. MPV, PDW, and PCT were measured in the studied groups. RESULTS: The MPV levels were significantly altered in Group 1, Group 2, and Group 3 patients when compared with those in the controls (P<0.05), whereas PDW and PCT levels were not significantly changed among groups (P>0.05). CONCLUSION: The data provided a significant association between MPV levels and DM. Diabetic patients have increased MPV values compared with healthy subjects, but MPV levels were not altered together with the DR stage. Diabetic and DR patients have no different PDW and PCT values compared with healthy subjects. MPV may be a clue for the reflection of subclinical platelet activation in DM regardless of the DR stage.

Plateletcrit. A platelet marker associated with saphenous vein graft disease.

BACKGROUND: Saphenous vein graft disease (SVGD) after by-pass surgery is an important cause of morbidity and mortality for patients with coronary artery disease. Comprehensive evaluation of biochemical and hematological parameters associated with this problem is limited. Plateletcrit (PCT) provides complete information on total platelet mass, but it has not been previously studied. In this study, we examined the relationship between SVGD and platelet parameters such as PCT, mean platelet volume, platelet count, and platelet distribution. METHODS: We retrospectively analyzed 14,398 patients who underwent coronary angiography between February 2006 and August 2012. Records from 893 patients with previous coronary artery by-pass graft operation were re-evaluated. A total of 251 cases were divided into two groups (127 patients receiving a saphenous vein graft; 124 patients diagnosed with SVGD) and hematological and biochemical parameters were compared. RESULTS: There were no significant differences in clinical characteristics between the two groups except that the SVGD group had a higher median time from surgery to coronary angiography than the patent saphenous vein graft group [7 years (2-16) vs. 5 years (2-15), p < 0.001]. The SVGD groups also had significantly higher median PCT, mean platelet volume, platelet count, uric acid level, and red blood cell distribution width. The cut-off value for PCT was found to be 0.188 for predicting SVGD, with an 80.65 % sensitivity and 81.1 % specificity. CONCLUSION: Plateletcrit has an important predictive value for SVGD, and it could be used as a marker for anti-platelet therapy to prevent graft atherosclerosis in patients undergoing by-pass surgery.

Iron deficiency can cause cognitive impairment in geriatric patients.

OBJECTIVES: Deficiency of iron, which plays an important role in oxygen transport and storage, may lead to cerebral hypoxia and cognitive decline. This relationship which was studied in children and adults was not evaluated in the elderly. The objective of this study is to examine the effect of iron deficiency on cognitive function in the elderly. DESIGN, SETTING, PARTICIPANTS: This is a cross-sectional study conducted in a geriatric medicine outpatient clinic of a university hospital. Consecutive 2009 patients admitted to Geriatric Medicine outpatient clinic were examined and 622 patients who fulfilled the inclusion criteria were enrolled in the study. MEASUREMENTS: Comprehensive geriatric assessment, cognitive assessment and laboratory analysis including blood count, iron, total iron binding capacity, ferritin, and transferrin saturation were performed. RESULTS: Mean age of the study group was 72.5±6.5 and 439 (70.6%) were women. MMSE scores were moderately and significantly correlated with iron levels (r=0.33, p<0.001) and transferrin saturation (r=0.32, p<0.001). Transferrin saturation was significantly lower in the patients with dementia (p=0.040). It was found that patients with iron deficiency had lower MMSE scores (p<0.001) and this relationship was also present in patients without anemia (p=0.004). CONCLUSION: The results of this study revealed a negative influence of iron deficiency on cognitive function and this influence was independent from the presence of anemia. As iron deficiency can be easily diagnosed and treated, detecting its effect on cognitive function is of importance. Screening for iron deficiency and initiating appropriate treatment should be a routine part of comprehensive geriatric assessment.

Beneficial effects of Ankaferd Blood Stopper on caustic esophageal injuries: an experimental model.

Ankaferd Blood Stopper (ABS) is an herbal extract that enhances mucosal healing. The aim of this study was to investigate the efficacy of ABS on the healing of the esophagus and prevention of stricture development after esophageal caustic injuries in rats. The study included 50 rats. Rats were divided into five groups: group 1 (no injury, sham surgery), group 2 (injury + no ABS + study after 2 weeks of injury), group 3 (injury + ABS + study after 2 weeks of injury), group 4 (injury + no ABS + study after 4 weeks of injury), and group 5 (injury + ABS + study after 4 weeks of injury). Standard esophageal burn injury was created by applying 50% NaOH solution to distal esophagus of about 1.5 cm. To rats in the sham group, isotonic solution was given instead of NaOH. ABS (2 mL/day) was given via oral route to group 3 and 5 rats. Fourteen days (group 2 and 3) and 28 days (group 4 and 5) later, all the live rats were killed. The distal esophageal segments of all rats were removed and divided into two equal parts for biochemical and histopathological examination. Mortality rate, weight changes, inflammation, stenosis index (SI), and biochemical measurements were evaluated. The SI was found as 0.31 ± 0.03 in group 1, 0.533 ± 0.240 in group 2, 0.568 ± 0.371 in group 3, 0.523 ± 0.164 in group 4, and 0.28 ± 0.03 in group 5. The SI and inflammation in ABS-treatment group 5 was significantly lower than that in non-treatment group 4 (P= 0.005). There were no significant differences between inflammation and SI among other groups. The mortality rate was 14.2% in group 1, 37.5% in untreated group 2, 14.2% in ABS-treated group 3, 80% in untreated group 4, and 33.3% in ABS-treated group 5. The mortality rate in group 4 was significantly higher than other groups (P= 0.025). Decrease rates in mean body weights of the groups were as follows: group 1, 1%; group 2, 15%; group 3, 14%; group 4, 46%; and group 5, 15%. Biochemical tests other than albumin and creatinine were comparable among the groups. Treatment with ABS prevents inflammation, scar formation, weight loss, and mortality in esophageal caustic injuries. Additional studies to evaluate the clinical benefits of ABS in esophageal caustic injury are recommended.

Use of Ankaferd Blood Stopper for controlling actively bleeding fundal varices.

Variceal bleeding is one of the most important and life-threatening complications of portal hypertension. Although less common than oesophageal varices that have a lower frequency of bleeding, gastric varices tend to result in more severe and mortal bleeding. The Ankaferd Blood Stopper (ABS) has been used with varying success in recent years for the management of bleeding from skin lesions or after dental surgery, and in other clinical conditions in which conventional haemostatic measures have proved to be deficient. In serious bleeding gastric fundal varices, ABS can also act as a bridge in the absence or unavailability of definitive therapies.

Allografting for Bosutinib, Imatinib, Nilotinib, Dasatinib, and Interferon Resistant Chronic Myeloid Leukemia without ABL Kinase Mutation.

The current treatment of chronic phase chronic myeloid leukemia (CML) consists of oral tyrosine kinase inhibitors (TKIs). However, high-risk CML may present with an aggressive course which may result in blastic crisis or a "difficult-to-manage" state with available treatments. The aim of this paper is to report a patient with complicated CML resistant to treatment and progressed despite the administration of bosutinib, imatinib mesylate, nilotinib, dasatinib, interferon alpha 2a, cytotoxic chemotherapy, and allogeneic hematopoietic stem cell transplantation. The striking point of this case story is that no Abl kinase domain mutation against TKIs has been detected during this very complicated disease course of CML. Meanwhile, challenging cases will always be present despite the hope and progress in CML in the TKI era.

Potential biomarkers for vascular damage in Alzheimer's disease: thrombomodulin and von Willebrand factor.

OBJECTIVES: Evidence regarding the vascular basis of Alzheimer's disease (AD) is growing. In vascular damage thrombomodulin tears of the cell wall and its level increases in the plasma. von Willebrand factor (vWF) is also thought to be a biomarker for vascular damage. The aim of this study was to examine the levels of vWF and thrombomodulin in AD as possible markers for vascular damage and to test their utility as an early biomarker in AD. DESIGN: Case-control study. SETTING: Geriatric medicine outpatient clinic of a university hospital. PARTICIPANTS: Twenty Alzheimer's disease patients free from vascular risk factors and 20 controls were enrolled in the study. MEASUREMENTS: Thrombomodulin and VWF levels of 20 AD patients and 20 controls were analyzed by commercial kits. RESULTS: Thrombomodulin levels were not different between Alzheimer's disease and control groups [median (range) = 4.25 (2.27-37.00) ng/ml in Alzheimer's disease and 3.55 (2.27-14.00) in control group, p=0.15]. Von Willebrand Factor antigen (%) levels were 188.5 (96-306) in Alzheimer's disease, and 181 (112- 284) in control group (p=0.74). CONCLUSION: Although vascular damage is thought to play role in the pathogenesis of AD, vWF and thrombomodulin failed to demonstrate the vascular damage in AD. Their utility to be used as early biomarkers of AD could not be shown.

Effects of imatinib mesylate on renin-angiotensin system (RAS) activity during the clinical course of chronic myeloid leukaemia.

The renin-angiotensin system (RAS) is involved in cell growth, proliferation and differentiation in bone marrow in an autocrine-paracrine manner, and it modulates normal and neoplastic haematopoietic cell proliferation. This study aimed to assess expressions of the RAS components, renin, angiotensinogen and angiotensin-converting enzyme (ACE), during imatinib mesylate treatment of patients with chronic myeloid leukaemia (CML). Expressions of RAS components were studied in patients with CML at the time of diagnosis (n = 83) and at 3, 6 and 12 months after diagnosis (n = 35) by quantitative real-time polymerase chain reaction. De novo CML patients had increased ACE, angiotensinogen and renin mRNA levels and these expression levels decreased following administration of imatinib. The RAS activities were significantly different among Sokal risk groups of CML, highlighting the altered biological activity of RAS in neoplastic disorders. The results of this study confirm that haematopoietic RAS affects neoplastic cell production, which may be altered via administration of tyrosine kinase inhibitors such as imatinib mesylate.

Basic parameters of thrombophilia in ocular Behçet disease with posterior segment involvement.

AIM: To assess basic thrombophilic parameters in both active and inactive periods of the ocular Behçet disease (BD) with posterior segment involvement in comparison with those in healthy adults as controls. METHOD: Thirty patients within the active period of the ocular BD with posterior segment involvement, 30 patients within the inactive period of the ocular BD with posterior segment involvement and 30 age-and sex-matched healthy controls were included in the study. Plasma protein C, free protein S, antithrombin III and activated protein C resistance were measured in the studied groups. RESULTS: Activated protein C resistance and antithrombin III levels were significantly altered in both active and inactive ocular BD patients when compared with those in the controls (p<0.05), whereas protein C and free protein S levels were not significantly changed within both groups (p>0.05). There was no difference among the active and inactive groups of BD for all of the studied blood tests (p>0.05). CONCLUSION: Activated protein C resistance together with increased antithrombin III plasma levels are associated with the posterior segment involvement in ocular BD based on the assessment of basic thrombophilic tests.

Haemostatic actions of the folkloric medicinal plant extract Ankaferd Blood Stopper.

Ankaferd Blood Stopper (ABS), a standardized mixture of five plants, has been used historically as a haemostatic agent but its mechanism of action remains unknown. This study investigated the in vitro effects of ABS on haemostatic parameters. When added to plasma or serum, ABS induced the very rapid formation of a protein network and erythrocyte aggregation. The levels of coagulation factors II, V, VII, VIII, IX, X, XI, and XIII were not affected by ABS. Plasma fibrinogen activity and antigen levels were decreased following the addition of ABS, in parallel with the prolonged thrombin time. Total protein, albumin, and globulin levels decreased after the addition of ABS. Our findings suggest that ABS stimulates the formation of an encapsulated protein network that provides focal points for erythrocyte aggregation. ABS has the therapeutic potential to be used for the management of haemorrhage and this agent should be investigated further in clinical trials.