We included 222 males and 212 females with similar mean ages (30.8 vs 30.3 years, p>0.05, respectively), and there was no patient above the age of 59 years. Associated TM were detected with similar prevalences in both genders (72.5% vs 67.9%, p>0.05, respectively). Smoking (23.8% vs 6.1%) and alcohol (4.9% vs 0.4%) were both higher in males (p<0>Table 1). Transfused units of RBC in their lives (48.1 vs 28.5, p=0.000), AIHA (4.0% vs 1.8%, p<0>p<0>p<0>p<0>p<0>p<0>p<0>p<0>p<0>p<0>Table 2). On the other hand, the mean ages of the atherosclerotic endpoints were shown in Table 3.

Excess fat tissue may be the major cause of vasculitis, aging, and death, and overweight, obesity, and morbid obesity may be irreversible atherosclerotic endpoints in human body. Excess fat tissue causes both excess external pressure on and internal narrowing of vasculature in addition to the already increased blood and insulin needs of the excess tissue. DM may be an irreversible atherosclerotic endpoint caused by the excess fat tissue in whole body rather than the pancreas alone. Although all kinds of atherosclerotic consequences are so common with the SCD, we detected no case of DM in the present study probably due to the lesser excess fat tissue in them. The body mass indexes (BMI) were 20.7 vs 24.9 kg/m2 in the SCD and control groups with the mean age of 28.6 years, respectively (p= 0.000) [11]. The body heights were similar in both groups (166.1 vs 168.5 cm, respectively, p>0.05) indicating that the height is determined, genetically [11]. Similarly, just 20% of elderly have DM, but 55% of patients with DM are obese. So excess fat tissue may be much more risky than aging, smoking, alcohol, or chronic inflammatory or infectious processes for DM. Excess fat tissue leads to a chronic and low-grade inflammation on vascular endothelium, and risk of death from all causes increases parallel to its severity [20]. The low-grade chronic inflammation may also cause genetic changes on the endothelial cells, and the systemic atherosclerotic process may even decrease clearance of malignant cells by the natural killers [21]. The chronic inflammatory process is characterized by lipid-induced injury, invasion of macrophages, proliferation of smooth muscle cells, endothelial dysfunction, and increased atherogenicity [22, 23]. Excess fat tissue is considered as a strong factor for controlling of C-reactive protein (CRP) because the excess tissue produces biologically active leptin, tumor necrosis factor-alpha, plasminogen activator inhibitor-1, and adiponectin-like cytokines [24, 25]. On the other hand, excess fat tissue will also aggravate myocardial hypertrophy and decrease cardiac compliance. Fasting plasma glucose (FPG), triglycerides, and low density lipoproteins (LDL) increased and high density lipoproteins (HDL) decreased parallel to the increased BMI [26]. Similarly, CHD and stroke increased parallel to the increased BMI [27]. Finally, the risk of death from all causes increased parallel to the increased excess fat tissue in all age groups, and people with underweight may even have lower biological ages and longer overall survival [4]. Similarly, calorie restriction prolongs survival and retards age-related chronic sicknesses [28]. So the term of excess weight should be replaced with the amount of excess fat tissue in human body since there are approximately 19 kg of excess fat tissue even between the lower and upper borders of normal weight, 33 kg between the lower borders of normal weight and obesity, and 66 kg between the lower borders of normal weight and morbid obesity (BMI ≥ 40 kg/m2) in adults. Interestingly, overweight and obesity are usually started to develop in early childhood. Actually, excess fat tissue may not be an indicator of overeating instead it may just show relative physical and mental inactivity. In another definition, excess fat tissue may be a problem of movement instead of eating. People with hyperactivity and normal weight may even eat much higher than people with overweight or obesity. It is well known that the physical and mental activities increase insulin sensitivity, and prevent development of DM, HT, and other atherosclerotic consequences. But the physical and mental activities should be regular and continuous. Actually, they should be the routine habits of life such as walking even in moderate distances, not using elevator, not using dishwasher, preparing meal at home, plant nutrition, self cleaning of home or workplaces, getting a family and children, spending time with the family members, getting a regular job, trying to do some repairs by themselves, avoiding of retirement as much as possible, getting some daily, weekly, monthly, yearly, and decadely aims to live for an endless life, asking questions about what I did today and what will I do tomorrow just before sleeping, etc. In another definition, people must be engaged into the life with several logical aims. On the other hand, the overweight, obesity, and morbid obesity may be irreversible because getting weight decreases physical activities, and decreased physical activities bring excess fat tissue further. Thus the fighting with excess fat should be started even in early childhood, and the main targets should be the increased mental and physical activities instead of the decreased eating alone. In another definition, people can eat how much they can burn. DM is the most common cause of blindness, non-traumatic amputation, and hemodialysis in adults. As the most common cause of CRD, DM may be an irreversible atherosclerotic consequence affecting the pancreas, too. Increased blood and insulin needs of the excess fat tissue in contrast to the decreased blood supply of the excess tissue and pancreas both due to excess external pressure on and internal narrowing of the vasculature may be the underlying mechanisms of DM. For example, excess fat tissue in the liver and pancreas are called as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic fatty pancreas disease (NAFPD). They are usually accepted as the components of the metabolic syndrome. NAFLD progresses to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Blocking triglycerides secretion, subcellular lipid sequestration, lipolysis deficiency, enhanced lipogenesis, gluconeogenesis defects, or inhibition of fatty acid oxidation may be some of the development mechanisms [29]. NAFLD may just be an atherosclerotic process, and strongly associated with an accelerated atherosclerotic process not only in the liver instead in whole body. For example, NAFLD is seen in one-third of cases with hepatitis B virus-related chronic liver disease [30]. Similarly, higher fatty liver ratios were observed in children with non-Hodgkin lymphomas [31]. The liver density on contrast abdominopelvic CT of colorectal cancer patients was low that is consistent with the NAFLD [32]. As one of the APR, serum thrombopoietin levels increased in the NAFLD [33]. Although serum levels of oxidizing agents including nitrate and advanced oxidation protein products increased, serum nitrite did not adequately increase as an antioxidant agent in the NAFLD [34]. As a result, NAFLD is associated with an impaired carotid intima-media thickness (IMT) and flow-mediated dilation which are considered as early markers of systemic atherosclerosis [35]. Carotid IMT was correlated with the BMI (p<0>p= 0.001), and grade 2-3 NAFLD (p<0>p<0>p<0>

Together with the RBC supports in acute stress and emergencies, hydroxyurea is the major life-saving regimen for the SCD [75]. It interferes with the cell division by blocking the formation of deoxyribonucleotides via the inhibition of ribonucleotide reductase. The deoxyribonucleotides are the building blocks of DNA. Hydroxyurea mainly affects hyperproliferating cells, and its main action may be the suppression of leukocytosis and thrombocytosis by blocking the DNA synthesis [76, 77]. Due to the same action way, hydroxyurea is also used in moderate and severe psoriasis to suppress hyperproliferating skin cells. As in the viral hepatitis cases, although presence of a continuous damage of sickle cells on the capillary endothelium, the severity of catastrophic process is probably exaggerated by the WBC and PLT. So suppression of proliferation of them can limit the endothelial damage-induced edema, ischemia, and infarctions [78]. Similarly, Hb F levels in hydroxyurea users did not differ from their pretreatment levels [79]. The Multicenter Study of Hydroxyurea (MSH) studied 299 severely affected adults with the SCA, and compared the results of patients treated with hydroxyurea or placebo [80]. The study particularly researched effects of hydroxyurea on painful crises, ACS, and need of RBC transfusion. The outcomes were so overwhelming in the favour of hydroxyurea group that the study was terminated after 22 months, and hydroxyurea was initiated for all patients. The MSH also demonstrated that patients treated with hydroxyurea had a 44?crease in hospitalizations [80]. In multivariable analyses, there was a strong and independent association of lower neutrophil counts with the lower crisis rates [80]. But this study was performed just in severe SCA cases alone, and the rate of painful crises was decreased from 4.5 to 2.5, annually [80]. Whereas we used all subtypes of the SCD with all clinical severity, and the rate of painful crises was decreased from 10.3 to 1.7, annually (p<0>p<0>p= 0.004) and mortality (p<0>p>0.05) in patients with AF and non-end-stage CRD [96]. Warfarin is associated with significant reductions in ischemic stroke even in patients with warfarin-associated intracranial hemorrhage (ICH) [97]. On the other hand, patients with cerebral venous thrombosis (CVT) anticoagulated either with warfarin or dabigatran had lower risk of recurrent venous thrombotic events (VTE), and the risks of bleeding were similar in both regimens (98). Additionally, an INR value of 1.5 achieved with an average daily dose of 4.6 mg warfarin, has resulted with no increase in the number of men ever reporting minor bleeding episodes [99]. Non-rheumatic AF increases the risk of stroke, and long-term use of low-dose warfarin is highly effective and safe with a reduction of 86% (p= 0.0022) (100). The mortality rate was significantly lower in the warfarin group, too (p= 0.005) (100). The frequencies of bleedings that required hospitalization or transfusions were similar in both groups (p>0.05) [100]. Additionally, very-low-dose warfarin was safe and effective for prevention of thromboembolism in metastatic breast cancer in which the average daily dose was 2.6 mg, and the mean INR value was 1.5 [101]. On the other hand, new oral anticoagulants had a favourable risk-benefit profile with significant reductions in stroke, ICH, and mortality, and with similar major bleedings as for warfarin, but increased GI bleeding [102]. Interestingly, rivaroxaban and low-dose apixaban were associated with increased risks of all cause mortality compared with warfarin [103]. The mortality rates were 4.1%, 3.7%, and 3.6% per year in the warfarin, 110 mg of dabigatran, and 150 mg of dabigatran groups with AF, respectively (p>0.05 for both) [104]. Eventually, infection, inflammation, medical or surgical emergency, and emotional stress-induced increased basal metabolic rate accelerates sickling, and an exaggerated capillary endothelial edema-induced myocardial infarction or stroke may cause sudden deaths [105]. So anti-inflammatory dose of aspirin plus low-dose warfarin may be the other life-saving regimen even at childhood in the SCD [106].

COPD is the third leading cause of death at the moment [107]. Aging, smoking, alcohol, male gender, excess fat tissue, chronic inflammation, prolonged infection, and cancers may be the underlying causes. Atherosclerotic effects of smoking may be the most obvious in the COPD and Buerger’s disease, probably due to the higher concentrations of toxic substances in the lungs and pooling of blood in the extremities. After smoking, excess fat tissue may be the second common cause of COPD due to the excess fat tissue-induced atherosclerotic endpoints in whole body since an estimated 25-45% of patients with the COPD have never smoked [108]. Regular alcohol consumption may be the third leading cause of the systemic exaggerated atherosclerotic process and COPD, since COPD was one of the most common diagnoses in alcohol dependence [109]. Furthermore, 30-day readmission rates were higher in the COPD patients with alcoholism [110]. Probably an accelerated atherosclerotic process is the main structural background of functional changes that are characteristics of the COPD. The inflammatory process of vascular endothelial cells is exaggerated by release of various chemicals by inflammatory cells, and it terminates with an advanced fibrosis, atherosclerosis, and pulmonary losses. COPD may just be the pulmonary endpoint of the systemic atherosclerotic process since there are several reports about coexistence of associated endothelial inflammation in whole body in the COPD [111]. For example, there may be close relationships between COPD, CHD, PAD, and stroke [112]. Furthermore, two-third of mortality cases were caused by cardiovascular diseases and lung cancers in the COPD, and the CHD was the most common cause in a multicenter study of 5.887 smokers [113]. When hospitalizations were researched, the most common causes were the cardiovascular diseases, again [113]. In another study, 27% of mortality cases were due to the cardiovascular diseases in the moderate and severe COPD [114]. Finally, COPD may be an irreversible atherosclerotic endpoint in the SCD, too [107]. Leg ulcers are seen in 10% to 20% of patients with the SCD, and its prevalence increases with aging, male gender, and SCA [115, 116]. The leg ulcers have an intractable nature, and around 97% of them relapse in one year [115]. Similar to Buerger's disease, the leg ulcers occur in the distal segments of the body with a lesser collateral blood flow [115]. The hardened RBC-induced chronic endothelial damage, inflammation, edema, and fibrosis at the capillaries may be the main causes [116]. Prolonged exposure to the hardened bodies due to the pooling of blood in the lower extremities may also explain the leg but not arm ulcers in the SCD. The hardened RBC-induced venous insufficiencies may also accelerate the process by pooling of causative bodies in the legs, and vice versa. Pooling of blood may also be important for the development of venous ulcers, diabetic ulcers, Buerger’s disease, digital clubbing, and onychomycosis in the lower extremities. Furthermore, pooling of blood may be the cause of delayed wound and fracture healings in the lower extremities. Smoking and alcohol probably have some additional atherosclerotic effects on the leg ulcers in males. Although presence of a continuous damage of hardened RBC on vascular endothelial cells, severity of the destructive process is probably exaggerated by the immune system. The main action way of hydroxyurea may be the suppression of hyperproliferative WBC and PLT in the SCD [78]. Similarly, lower WBC counts were associated with lower crisis rates, and if a tissue infarct occurs, lower WBC counts may decrease severity of tissue damage and pain [79]. Prolonged resolution of leg ulcers with hydroxyurea may suggest that the ulcers may be due to the increased WBC and PLT counts-induced capillary endothelial edema. Digital clubbing is characterized by the increased normal angle of 165° between the nailbed and fold, increased convexity of the nail fold, and thickening of the whole distal finger [117]. The chronic tissue hypoxia is highly suspected in its etiology [118]. In the previous study, only 40% of clubbing cases turned out to have significant underlying diseases while 60% remained well over the subsequent years [19]. But according to our experiences, digital clubbing is frequently associated with the smoking and pulmonary, cardiac, renal, and hepatic diseases which are characterized with chronic tissue hypoxia [6]. As an explanation for that hypothesis, lungs, heart, kidneys, and liver are closely related organs those can affect their functions in a short period of time. On the other hand, digital clubbing is also common in the SCD, too and its prevalence is 10.8% in the present study. It probably shows chronic tissue hypoxia caused by disseminated endothelial damage, edema, and fibrosis, particularly at the capillary level in the SCD. Beside the effects of SCD, smoking, alcohol, cirrhosis, CRD, CHD, and COPD, the higher prevalence of clubbing in males (14.8% vs 6.6%, p<0>p= 0.04), high-sensitivity CRP (p= 0.01), mean arterial BP (p= 0.003), and DM (p= 0.02) had significant correlations with the CIMT [119]. Increased renal tubular sodium reabsorption, impaired pressure natriuresis, volume expansion due to the activations of sympathetic nervous system and renin-angiotensin system, and physical compression of kidneys by visceral fat tissue may be some mechanisms of the increased BP with excess fat tissue [122]. Excess fat tissue also causes renal vasodilation and glomerular hyperfiltration which initially serve as compensatory mechanisms to maintain sodium balance due to the increased tubular reabsorption [122]. However, along with the increased BP, these changes cause chronic endothelial damage in kidneys in long term [123]. With prolonged excess fat tissue, there are increased urinary protein excretion, loss of nephron function, and exacerbated HT. With the development of dyslipidemia and DM, CRD progresses more easily [122]. The systemic inflammatory effects of smoking on endothelial cells is also important in the CRD [124]. Although the presence of some opposite reports [124], alcohol probably gives harm to the renal vascular endothelium, too. Chronic inflammatory or infectious processes may terminate with atherosclerotic endpoints in kidneys, too [123]. There are close relationships between CRD and other atherosclerotic endpoints [125, 126]. The most common causes of death were CHD and stroke in the CRD, again [127]. The hardened RBC-induced capillary endothelial damage may be the cause of CRD in the SCD [128]. Stroke is the other terminal cause of death after the CHD, and it develops as an acute thromboembolic event on the chronic atherosclerotic background. Aging, male gender, smoking, alcohol, excess fat tissue, chronic inflammatory or infectious process, cancer, and emotional stress may be the major causes. Stroke is also a common atherosclerotic endpoint of the SCD [129]. Similar to the leg ulcers, stroke is particularly higher in cases with the SCA and higher WBC counts [130]. Sickling-induced capillary endothelial damage, activations of WBC, PLT, and coagulation system, and hemolysis may terminate with chronic capillary endothelial damage, edema, and fibrosis [131]. Stroke may not have a macrovascular origin instead a diffuse capillary endothelial edema may be important in the SCD. Thus permanent neurological deficits are rare with stroke in the SCD. Infection, inflammation, medical or surgical emergency, and emotional stress may cause stroke by increasing basal metabolic rate and sickling. Low risk of stroke with hydroxyurea can also suggest that a significant proportion of stroke is developed due to the increased WBC and PLT counts-induced an acute capillary endothelial edema [132]. Acarbose is a pseudotetrasaccharide produced as a natural microbial product of Actinoplanes strain SE 50. It binds to oligosaccharide binding site of alpha-glucosidase in the brush border of the small intestinal mucosa with a dose-dependent manner, reversibly and competitively. It inhibits glycoamylase, sucrase, maltase, dextranase, and pancreatic alpha-amylase. It has little affinity for isomaltase but does not have any effect on beta-glucosidases such as lactase. By this way, it delays the intestinal hydrolysis of oligo- and disaccharides mainly in the upper half of the small intestine. As a result, the absorption of monosaccharides is delayed, and transport into the circulation is interrupted. Its effects may prolong up to 5 hours. The suppression of alpha-glucosidases is persistent with long-term use. Its usage results with carbohydrates appearing in the colon where bacterial fermentation occurs, and causes flatulence, loose stool, and abdominal discomfort [133]. If started with a lower dosage and titrated slowly, side effects are tolerable [134]. Long-term use increases colonic bacterial mass that of lactobacteria in particular. The finally impaired carbohydrate absorption, increased bacterial carbohydrate fermentation, and fecal acidification mimic effects of lactulose in portosystemic encephalopathy. So acarbose has a favourable therapeutic profile for the long-term use even in cirrhosis. Similarly, observed changes in bacterial flora and decreased stool pH and beta-hydroxybutyrate may be associated with anti-proliferative effects on the epithelial cells of colon that may potentially decrease carcinogenesis. Less than 2% of the unchanged drug enters into the circulation. Thus there is no need for dosage adjustment in mild renal insufficiency. After a high carbohydrate meal, acarbose lowers the postprandial rise in blood glucose by 20% and secondarily FPG by 15% [135]. The initial improvement in blood glucose tends to be modest, but efficacy steadily improves. It also affects serum lipids with a dose-dependent manner, because dietary carbohydrates are key precursors of lipogenesis [135]. Carbohydrate-induced postprandial triglycerides synthesis is reduced for several hours, so acarbose lowers triglycerides [135]. The same effect is also seen in non-diabetic patients with hypertriglyceridemia, and acarbose reduced LDL, and HDL remained as unchanged in hyperinsulinemic and overweight patients with impaired glucose tolerance (IGT) [136]. Elevated ursocholic acids in the stool appear to be the additive endpoint of a decreased rate of absorption and increased intestinal motility due to the changes of intestinal flora. Acarbose may lower LDL via increased fecal bifido bacteria and biliary acids. Acarbose together with insulin was identified to be associated with a greater improvement in the oxidative stress and inflammation [137]. Probably, acarbose improves release of glucagon-like peptide-1, inhibits PLT activation, increases epithelial nitrous oxide synthase activity and nitrous oxide concentrations, promotes weight loss, decreases BP, and eventually prevents endothelial dysfunction [135]. So it prevents atherosclerotic endpoints of excess fat tissue even in the absence of IGT or DM [138, 139]. Although some authors reported as opposite [140], it should be used as the first-line antidiabetic agent. Based on more than 40 years of use, numerous studies did not show any significant side effect [141]. Although 25.9% of patients stopped metformin due to excessive anorexia [142], only 10.6% stopped acarbose due to excessive flatulence or loose stool [143]. Metformin is a biguanide, and it is not metabolized, and 90% of absorbed drug is eliminated as unchanged in the urine. Plasma protein binding is negligible, so the drug is dialyzable. According to literature, antihyperglycemic effect of metformin is largely caused by inhibition of hepatic gluconeogenesis, increased insulin-mediated glucose disposal, inhibition of fatty acid oxidation, and reduction of intestinal glucose absorption [144, 145]. Precise mechanism of intracellular action of metformin remains as unknown. Interestingly, 25.9% of patients stopped metformin due to the excessively lost appetite [142]. Additionally, 14.1% of patients with overweight or obesity in the metformin group rose either to normal weight or overweight group by weight loss without a diet regimen [142]. According to our opinion, the major effect of metformin is an inhibition of appetite. Similar results indicating the beneficial effects on the BMI, BP, FPG, and lipids were also reported [146]. Probably the major component of the metabolic syndrome may be the excess fat tissue. So treatment with acarbose plus metformin will probably prevent not only IGT or DM but also the other atherosclerotic endpoints [147, 148]. As a conclusion, hardened RBC-induced capillary endothelial damage terminates with end-organ insufficiencies in early decades in SCD. The increased basal metabolic rate during stresses aggravates the sickling and capillary endothelial edema, terminating with tissue infarcts. So the risk of mortality is much higher during acute painful crises. The deaths seem sudden and unexpected, and most of them develop just after hospital admission in patients without hydroxyurea therapy. Rapid RBC supports are life-saving but preparation of RBC takes time. Beside that RBC supports in emergencies become much more difficult in terminal patients due to the previous transfusions-induced AIHA. Therefore, RBC transfusions should be preserved just for acute stress and emergencies due to the efficacy of hydroxyurea.