We studied 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 neither in male nor in females. Associated TM were detected with similar prevalences in male and females (72.5% vs 67.9%, p>0.05, respectively). Both smoking (23.8% vs 6.1%) and alcohol (4.9% vs 0.4%) were higher in males (p<0>Table 1). Transfused units of RBC in their lives (48.1 vs 28.5, p=0.000), disseminated teeth losses (5.4% vs 1.4%, p<0>p<0>p<0>p<0>p<0>p<0>p<0>p<0>p<0>Table 2). On the other hand, mean ages of the terminal atherosclerotic endpoints were shown in Table 3.

*Sickle cell diseases   †Nonsignificant (p>0.05)   ‡Red blood cells   §Coronary heart disease   ¶Chronic obstructive pulmonary disease   **Chronic renal disease   ***Pulmonary hypertension   ****Deep venous thrombosis   *****Acute chest syndrome

Table 2: Associated pathologies of the study patients

*Acute chest syndrome   †Chronic obstructive pulmonary disease   ‡Pulmonary hypertension   §Coronary heart disease  ¶Deep venous thrombosis   **Chronic renal disease

Table 3: Mean ages of endpoints of the sickle cell diseases

As an accelerated atherosclerotic process, hardened RBC-induced capillary endothelial damage initiated at birth terminates with multiorgan failures in early decades in SCD. Excess fat may be more important than smoking and alcohol for atherosclerosis since excess weight-induced diabetes mellitus is the most common cause of the CRD. The efficacy of acarbose to lower blood glucose by preventing breakdown of starch into sugar in the small intestine is well-known. Since acarbose is a safe, cheap, oral, long-term used, and effective drug for excess weight, it should be prescribed in prevention of stroke, particularly after the age of 50 years even in cases with normal weight because there are nearly 19 kg of excess fat even between the lower and upper borders of normal weight in adults.

Excess weight may be the most common cause of vasculitis, and actually the term should be replaced with excess fat tissue in the body. Probably, obesity is one of the terminal endpoints of the metabolic syndrome, since after development of obesity, nonpharmaceutical approaches provide little benefit either to reverse obesity or to prevent its endpoints. Excess fat tissue leads to a chronic and low-grade inflammation on vascular endothelium, and risk of death from all causes including cardiovascular diseases and cancers increases parallel to the range of excess fat tissue (19). The low-grade chronic inflammation may also cause genetic changes on the endothelial cells, and the systemic atherosclerosis may even decrease the clearance of malignant cells by the natural killers (20). The chronic inflammatory process is characterized by lipid-induced injury, invasion of macrophages, proliferation of smooth muscle cells, endothelial dysfunction, and increased atherogenicity (21, 22). Excess fat tissue is considered as a strong factor for controlling of C-reactive protein (CRP) concentration in serum, since excess fat tissue produces biologically active leptin, tumor necrosis factor-alpha, plasminogen activator inhibitor-1, and adiponectin-like cytokines (23, 24). On the other hand, individuals with excess fat tissue will also have an increased cardiac output. The prolonged increase in blood volume may aggravate myocardial hypertrophy and decrease cardiac compliance further. Beside the systemic atherosclerosis and HT, fasting plasma glucose (FPG) and serum cholesterol increased and high density lipoproteins (HDL) decreased parallel to the increased body mass index (BMI) (25). Similarly, CHD and stroke increased parallel to the increased BMI (26). Eventually, the risk of death from all causes increased parallel to the severity of excess fat tissue in all age groups, and the cases with underweight may even have lower biological ages and longer survival (27). Similarly, calorie restriction prolongs survival and retards age-related chronic illnesses in human being (28). Smoking may be the second most common cause of vasculitis all over the world. Probably, it causes a systemic inflammation on vascular endothelium terminating with an atherosclerosis-induced multiorgan failures in early decades of life (29). Its atherosclerotic effect is obvious in the Buerger’s disease and COPD (30). Buerger’s disease is an obliterative vasculitis in the small and medium-sized arteries and veins, and it has never been seen without smoking. Its characteristic features are inflammation, fibrosis, and narrowing and occlusions of arteries and veins. Claudication is the most common symptom with a severe pain caused by insufficient blood supply in feet and hands, particularly with exercise. It typically begins in extremities but it may also radiate to central areas in advanced cases. Numbness or tingling of the limbs is also common. Skin ulcerations and gangrene of fingers or toes are the terminal endpoints. Similar to the venous ulcers, diabetic ulcers, leg ulcers of the SCD, clubbing, onychomycosis, and delayed wound and fracture healings of the lower extremities, pooling of blood due to the gravity may be important in the development of Buerger's disease, particularly in the lower extremities. Multiple narrowings and occlusions in the arms and legs are diagnostic in the angiogram. Skin biopsies are rarely required since a poorly perfused area will not heal, completely. Although most patients are heavy smokers, the limited smoking history of some patients may support the hypothesis that Buerger's disease may be an autoimmune reaction triggered by some constituent of tobacco. Although the only treatment way is complete cessation of smoking, the already developed narrowing and occlusions are irreversible. Due to the obvious role of inflammation, anti-inflammatory dose of aspirin in addition to the low-dose warfarin may be effective in prevention of microvascular infarctions. On the other hand, FPG and HDL may be negative whereas triglycerides, low density lipoproteins (LDL), erythrocyte sedimentation rate, and CRP may be positive acute phase reactants in smokers (31). Similarly, smoking was associated with the lower BMI values due to the systemic inflammatory effects (32, 33). An increased heart rate was detected just after smoking even at rest (34). Nicotine supplied by patch after smoking cessation decreased caloric intake in a dose-related manner (35). Nicotine may lengthen intermeal time, and decrease amount of meal eaten (36). Smoking may be associated with a postcessation weight gain, but the risk is the highest during the first year, and decreases with the following years (37). Although the CHD was detected with similar prevalences in both genders, prevalences of smoking and COPD were higher in males against the higher prevalences of white coat hypertension, BMI, LDL, triglycerides, HT, and DM in females (38). The prevalence of myocardial infarction is increased three-fold in men and six-fold in women with smoking, so smoking may be more dangerous for women probably due to the higher BMI (39). Several toxic substances found in the cigarette smoke can affect various organ systems. For example, smoking is usually associated with depression, irritable bowel syndrome (IBS), chronic gastritis, hemorrhoids, and urolithiasis with several underlying mechanisms (40). First of all, smoking may also have some antidepressive properties. Secondly, smoking-caused vascular inflammation may disturb epithelial functions for absorption and excretion in the gastrointestinal (GI) and genitourinary (GU) tracts (41). Thirdly, diarrheal losses-caused urinary changes may cause urolithiasis (42). Fourthly, smoking-caused sympathetic nervous system activation may induce motility problems in the GI and GU tracts terminating with IBS and urolithiasis. Finally, immunosuppression secondary to smoking-caused vascular inflammation may terminate with the GI and GU tract infections inducing urolithiasis because some types of bacteria can provoke urinary supersaturation, and modify the environment to form crystal deposits. Actually, 10% of urinary stones are struvite stones those are built by magnesium ammonium phosphate produced by the bacteria, producing urease. So, urolithiasis was seen in 17.9% of cases with IBS and 11.6% of cases without IBS (p<0>p<0>p<0>p= 0.004) and mortality (p<0>p>0.05) (79). Similarly, warfarin is associated with significant reductions in ischemic stroke even in patients with warfarin-associated intracranial hemorrhage (ICH) (80). Whereas recurrent ICH occured in 6.7% of patients who used warfarin and 7.7% of patients who did not use warfarin without any significant difference in between (p>0.05) (80). 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 (81). Additionally, an INR value of 1.5 achieved with an average daily dose of 4.6 mg warfarin, has resulted in no increase in the number of men ever reporting minor bleeding episodes (82). Non-rheumatic AF increases the risk of stroke, presumably from atrial thromboemboli, and long-term use of low-dose warfarin is highly effective and safe with a reduction of 86% in the risk of stroke (p= 0.0022) (83). The mortality was markedly lower in the warfarin group, too (p= 0.005) (83). The frequencies of bleedings that required hospitalization or transfusion were similar in both groups (p>0.05) (83). 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 (84). 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 (85). Interestingly, rivaroxaban and low-dose apixaban were associated with increased risks of all cause mortality compared with warfarin (86). 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 (p>0.05 for both) in AF in another study, respectively (87). On the other hand, infection, inflammation, medical or surgical emergency, and emotional stresses-induced increased basal metabolic rate accelerates sickling, and an exaggerated capillary endothelial edema-induced myocardial infarction and stroke may cause sudden deaths in the SCD (88). So lifelong aspirin with an anti-inflammatory dose plus low-dose warfarin may be a life-saving regimen even at childhood to decrease severity of capillary endothelial inflammation and to prevent thromboembolic events in them (89).COPD is the third leading cause of death in human being (90, 91). Aging, smoking, alcohol, male gender, excess fat tissue, chronic inflammation, prolonged infection, and cancers may be the major 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 process in whole body. Regular alcohol consumption may be the third leading cause of the systemic accelerated atherosclerotic process and COPD, since COPD was one of the most common diagnoses in alcohol dependence (92). Furthermore, 30-day readmission rates were higher in the COPD patients with alcoholism (93). Probably an accelerated atherosclerotic process is the main structural background of functional changes that are characteristics of the COPD. The inflammatory process of vascular endothelium is enhanced by release of various chemicals by inflammatory cells, and it terminates with an advanced fibrosis, atherosclerosis, and pulmonary losses. COPD may actually be the pulmonary endpoint of the systemic atherosclerotic process. Since beside the accelerated atherosclerotic process of the pulmonary vasculature, there are several reports about coexistence of associated endothelial inflammation all over the body in COPD (94). For example, there may be close relationships between COPD, CHD, PAD, and stroke (95). 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 multi-center study of 5.887 smokers (96). When the hospitalizations were researched, the most common causes were the cardiovascular diseases, again (96). In another study, 27% of mortality cases were due to the cardiovascular diseases in the moderate and severe COPD (97). On the other hand, COPD may be the pulmonary endpoint of the systemic atherosclerotic process caused by the hardened RBC in the SCD (90). Leg ulcers are seen in 10% to 20% of the SCD (98). Its prevalence increases with aging, male gender, and SCA (99). The leg ulcers have an intractable nature, and around 97% of them relapse in a period of one year (98). Similar to Buerger's disease, the leg ulcers occur in the distal segments of the body with a lesser collateral blood flow (98). The hardened RBC-induced chronic endothelial damage, inflammation, edema, and fibrosis at the capillaries may be the major causes (99). 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, 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 may also have some additional atherosclerotic effects on the leg ulcers in males. Hydroxyurea is the first drug that was approved by Food and Drug Administration in the SCD (100). It is an oral, cheap, safe, and effective drug that blocks cell division by suppressing formation of deoxyribonucleotides which are the building blocks of DNA (11). Its main action may be the suppression of hyperproliferative WBC and PLT in the SCD (101). Although presence of a continuous damage of hardened RBC on vascular endothelium, severity of the destructive process is probably exaggerated by immune systems. Similarly, lower WBC counts were associated with lower crises rates, and if a tissue infarct occurs, lower WBC counts may decrease severity of tissue damage and pain (62). Prolonged resolution of leg ulcers with hydroxyurea may also suggest that the ulcers may be secondary to increased WBC and PLT counts-induced exaggerated capillary endothelial inflammation and edema. Digital clubbing is characterized by the increased normal angle of 165° between nailbed and fold, increased convexity of the nail fold, and thickening of the whole distal finger (102). Although the exact cause and significance is unknown, the chronic tissue hypoxia is highly suspected (103). In the previous study, only 40% of clubbing cases turned out to have significant underlying diseases while 60% remained well over the subsequent years (18). But according to our experiences, digital clubbing is frequently associated with the pulmonary, cardiac, renal, and hepatic diseases and smoking which are characterized with chronic tissue hypoxia (5). As an explanation for that hypothesis, lungs, heart, kidneys, and liver are closely related organs which affect their functions in a short period of time. On the other hand, digital clubbing is also common in the SCD, and its prevalence was 10.8% in the present study. It probably shows chronic tissue hypoxia caused by disseminated endothelial damage, inflammation, edema, and fibrosis at the capillary level in the SCD. Beside the effects of SCD, smoking, alcohol, cirrhosis, CRD, CHD, and COPD, the higher prevalence of digital 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 (104). 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 weight (107). 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 (107). However, along with the increased BP, these changes cause a hemodynamic burden on the kidneys in long term that causes chronic endothelial damage (108). 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 much more easily (107). On the other hand, the systemic inflammatory effects of smoking on endothelial cells may also be important in the CRD (109). Although some authors reported that alcohol was not related with the CRD (109), various metabolites of alcohol circulate in blood vessels of kidneys and give harm to the endothelium. Chronic inflammatory or infectious processes may also terminate with the accelerated atherosclerosis in the renal vasculature (108). Due to the systemic nature of atherosclerosis, there are close relationships between CRD and other atherosclerotic endpoints of the metabolic syndrome including CHD, COPD, PAD, cirrhosis, and stroke (110, 111). For example, the most common causes of death were the CHD and stroke in the CRD, again (112). The hardened RBC-induced capillary endothelial damage may be the main cause of CRD in the SCD, again (113). Together with the CHD, stroke is the other final cause of death, and it develops as an acute thromboembolic event on the chronic atherosclerotic background. Aging, male gender alone, smoking, alcohol, excess fat tissue, chronic inflammatory or infectious processes, cancers, and excessive stress may be the major underlying causes. Stroke is also a common complication of the SCD (114). Similar to the leg ulcers, stroke is particularly higher in cases with the SCA and higher WBC counts (115). Sickling-induced capillary endothelial damage, activations of WBC, PLT, and coagulation system, and hemolysis may terminate with chronic capillary endothelial damage, inflammation, edema, and fibrosis (116). Probably, stroke does not have a macrovascular origin in the SCD, and diffuse capillary endothelial inflammation, edema, and fibrosis may be much more significant. Infection, inflammation, medical or surgical emergency, and emotional stresses may precipitate stroke by increasing basal metabolic rate and sickling. Decreased stroke with hydroxyurea can also suggest that a significant proportion of cases is developed due to the increased WBC and PLT counts-induced an accelerated capillary endothelial edema in the SCD (117). Acarbose, a pseudotetrasaccharide, is a natural microbial product of Actinoplanes strain SE 50. It is an alpha-glucosidase inhibitor. It binds to oligosaccharide binding site of alpha-glucosidase enzymes 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. As a result, it delays the intestinal hydrolysis of oligo- and disaccharides mainly in the upper half of the small intestine. By this way, the absorption of monosaccharides is delayed, and transport into the circulation is interrupted. Actually, it does not have any direct effect on absorption of glucose. Acarbose should be taken with the first bite of the meal, and its effects may prolong up to 5 hours. The suppression of alpha-glucosidases is persistent with long-term use. Up to now, acarbose failure has not been seen. Its usage results with carbohydrates appearing in the colon where bacterial fermentation occurs, accounting for the frequency and severity of GI adverse effects such as flatulence, loose stool, and abdominal discomfort (118). If started with a lower dose and titrated slowly, it tends to cause tolerable GI side effects (119). 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 cirrhosis and 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 the risk of carcinogenesis. After oral administration, less than 2% of the unchanged drug can enter 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% (120). Similarly, it lowers fasting and postprandial insulin levels. The initial improvement in blood glucose tends to be modest, but efficacy steadily improves with the long-term use, and is maintained over several years. Its beneficial effects on serum lipids were also documented with a dose-dependent manner (120), since dietary carbohydrates are key precursors of lipogenesis, and insulin plays a central role for postprandial lipid metabolism. Carbohydrate-induced postprandial triglyceride synthesis is reduced for several hours, so acarbose lowers plasma triglyceride levels (120). The same beneficial effect is also seen in non-diabetic patients with hypertriglyceridemia, and acarbose reduced LDL significantly, and HDL remained as unchanged in hyperinsulinemic and overweight patients with impaired glucose tolerance (IGT) (121). Significantly 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 serum 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 in type 2 DM (122). 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 (120). So it prevents stroke-like atherosclerotic endpoints of excess weight even in the absence of IGT or DM (123, 124). Although some authors reported as opposite (125), it should be used as the first-line antidiabetic agent together with metformin. Based on more than 40 years of clinical use, numerous studies did not show any significant toxicity or loss of appetite (126).As a conclusion, hardened RBC-induced capillary endothelial damage initiated at birth terminates with multiorgan failures in early decades of life in the SCD. Excess fat may be much more important than smoking and alcohol for atherosclerosis since excess weight-induced DM is the most common cause of the CRD. The efficacy of acarbose to lower blood glucose by preventing breakdown of starch into sugar in the small intestine is well-known. Since acarbose is a safe, cheap, oral, long-term used, and effective drug for excess weight, it should be prescribed in prevention of stroke, particularly after the age of 50 years even in cases with normal weight because there are nearly 19 kg of excess fat even between the lower and upper borders of normal weight in adults.