The study included 428 patients with the SCDs (207 females and 221 males) during the nine-year follow-up period. There were 71 patients (16.5%) with COPD. Mean age of the patients was significantly higher in the COPD group (32.8 versus 29.8 years, P=0.005). The male ratio was significantly higher in the COPD group, too (78.8% versus 46.2%, P<0.001). Smoking (35.2% versus 11.4%, P<0.001) and alcohol consumption (7.0% versus 1.9%, P<0.01) were also higher among the COPD cases. Prevalences of associated thalassemia minors were similar in both groups (76.0% versus 68.6% in the COPD group and other, respectively, P>0.05) (Table 1). Beside these, priapism (14.0% versus 3.0%, P<0.001), cirrhosis (8.4% versus 3.3%, P<0.05), leg ulcers (23.9% versus 12.0%, P<0.01), digital clubbing (25.3% versus 6.7%, P<0.001), CHD (23.9% versus 13.7%, P<0.05), CRD (15.4% versus 7.0%, P<0.01), and stroke (16.9% versus 8.1%, P<0.01) were all higher in the COPD group. Additionally, painful crises per year (5.3 versus 4.9), ileus (4.2% versus 3.9%), prominent teeth loss (4.2% versus 3.0%), pulmonary hypertension (12.6% versus 12.0%), varices (11.2% versus 5.3%), rheumatic heart disease (7.0% versus 6.1%), sinus arrhythmia (4.2% versus 3.0%), and mortality (8.4% versus 6.4%) were all higher among the COPD cases, too but the differences were nonsignificant probably due to the small sample size of the COPD group. Parallel to the above consequences, mean transfused RBC units in their lives were significantly higher among the COPD cases (63.8 versus 33.0, P=0.003). Probably due to the higher number of transfused RBC units in their lives, the mean age of mortality was significantly higher in the COPD group (38.3 versus 30.4 years, P=0.04) (Table 2). On the other hand, there was one patient (1.4%) with HBsAg positivity in the COPD group and 4 patients (1.1%) among the others (P>0.05), but HBV DNA was positive in none of them by polymerase chain reaction (PCR) method. Although antiHCV positivity was similar in both groups (4.2% versus 6.1% of the COPD patients and others, respectively, P>0.05), HCV RNA positivity was significantly higher in the COPD group (2.7% versus 0.5% of the COPD group and other, respectively, P<0.05) by PCR. On the other hand, there were three patients with the sickle cell retinopathy in the group without COPD.

Table 1: Characteristic features of the study cases

*Chronic obstructive pulmonary disease †Nonsignificant (P>0.05)

Table 2: Associated pathologies of the study cases
*Chronic obstructive pulmonary disease †Nonsignificant (P>0.05) ‡Red blood cell §Coronary heart disease Chronic renal disease **Acute chest syndrome

Chronic endothelial damage may be the most common type of vasculitis, and the leading cause of aging and mortality in human beings. Physical inactivity, weight gain, smoking, alcohol, prolonged infections, and chronic inflammatory processes including SCDs, rheumatologic disorders, and cancers may accelerate the process. Probably whole afferent vasculature including capillaries are mainly involved in the process. Much higher BP of the afferent vasculature may be the major underlying cause by inducing recurrent micro-injuries on endothelium. Thus the term of venosclerosis is not as famous as arteriosclerosis or atherosclerosis in the literature. Secondary to the chronic endothelial inflammation, edema, and fibrosis, vascular walls become thickened, their lumens are narrowed, and they lose their elastic nature that reduces blood flow and increases BP further. Although early withdrawal of causative factors may delay final consequences, after development of cirrhosis, COPD, CRD, CHD, PAD, or stroke, endothelial changes cannot be reversed completely due to the fibrotic nature of them (12).

SCDs are life-threatening hereditary disorders nearly affecting 100,000 individuals in the United States (13). As a difference from other causes of chronic endothelial damage, they probably keep vascular endothelium particularly at the capillary level (14), since the capillary system is the main distributor of the hard RBCs to the tissues. The hard cells induced chronic endothelial damage, inflammation, edema, and fibrosis build up an advanced atherosclerosis in younger ages of the patients. As a result, mean lifespans of the patients were 48 years in females and 42 years in males in the literature (15), whereas they were 33.6 and 30.8 years in the present study, respectively. The great differences may be due to delayed diagnosis of the diseases, delayed initiation of hydroxyurea therapy, and inadequate RBC supports in severe clinical conditions in our country. Actually, RBC supports must be given whenever there is evidence of clinical deterioration in the patients (16, 17). RBC supports decrease sickle cell concentration in circulation and suppress bone marrow about the production of abnormal RBCs. So they decrease sickling induced endothelial damage of organs in crises. According to our nine-year experience, simple and repeated transfusions are superior to RBC exchange. First of all, preparation of one or two units of RBC suspensions each time rather than preparation of six units or higher provides time for clinicians to prepare more units by preventing sudden death of such patients. Secondly, transfusions of one or two units of RBC suspensions each time decreases the severity of pain and relaxes anxiety of the patients and surroundings in a short period of time. Thirdly, transfusions of lesser units of RBC suspensions each time by means of simple transfusions will decrease transfusion-related complications in the future. Fourthly, transfusion of RBC suspensions in secondary health centers may prevent some deaths developed during transport to tertiary centers for the exchange. On the other hand, longer lifespan of females in the SCDs (15) and longer overall survival of females in the world (18) cannot be explained by the atherosclerotic effects of smoking and alcohol alone, instead it may be explained by physical power requiring role of males that may terminate with an exaggerated sickling and atherosclerosis all over the body (19).

COPD is the third leading cause of mortality with different underlying etiologies in the world (20). It is an inflammatory disorder mainly affecting the pulmonary vasculature, and smoking, excess weight, and aging may be the major causes. Regular alcohol consumption may also take place in the inflammatory process. For example, the prevalence of alcohol consumption was significantly higher in the COPD group (7.0% versus 1.9%, P<0.01), here. Similarly, COPD was one of the most frequent associated disorders in alcohol dependence in another study (21). Additionally, 30-day readmission rate was higher in COPD patients with alcoholism (22). Probably an accelerated atherosclerotic process is the main structural background of functional changes that are characteristics of COPD. The endothelial process is enhanced with release of various chemicals by inflammatory cells, and terminates with endothelial fibrosis and tissue loss in lungs. Although COPD may mainly be an accelerated atherosclerotic process of the pulmonary vasculature, there are several reports about coexistence of disseminated endothelial inflammation all over the body (23, 24). For example, close relationships were shown between COPD, CHD, PAD, and stroke (25). Similarly, two-thirds of mortality cases were caused by cardiovascular diseases and lung cancers in smokers in a multi-center study (26). When the hospitalizations were researched, the most common causes were the cardiovascular diseases again (26). In another study, 27% of all mortality was due to the cardiovascular causes in the moderate and severe COPD cases (27). Due to the strong atherosclerotic natures of the SCDs and COPD, COPD may be one of the terminal endpoints of the SCDs due to the higher prevalence of priapism, cirrhosis, leg ulcers, digital clubbing, CHD, CRD, and stroke in the COPD group, here.

Painful crises are the most disabling and nearly pathognomonic symptoms of the SCDs. For example, only 11.9% of the study cases (9.8% versus 12.3% in the COPD and other groups, respectively, P>0.05) have not had any painful crisis in their lives, here. Although the crises may not be life threatening directly (28), infections are the most common precipitating factors of them. The patients are immunocompromised due to a variety of reasons including a functional and anatomic asplenism, chronic endothelial damage induced end-organ failures, a permanent inflammatory process all over the body, hospitalizations, transfusions, and invasive procedures. Because of the deep immunodeficiency, simple infections may even progress to sepsis in a short period of time. Thus multiorgan failures and mortality are not rare during acute painful crises in them. Similarly, RBC supports may provide adequate tissue oxygenation and immunity, and so prevent intractable pain, dissemination of infections or inflammations, end-organ failures, and mortality during surgical operations, major depressions, and other severe clinical conditions. On the other hand, pain is the result of a yet poorly understood interaction between the hard cells, endothelial cells, white blood cells (WBC), and platelets (PLT). The adverse effects of WBCs and PLTs on endothelium are of particular interest. For example, leukocytosis even at the silent period was an independent predictor of severity of the SCDs (29), and it was associated with an increased risk of stroke (30). On the other hand, leukocytosis and thrombocytosis are acute phase reactants that are also present during the silent periods in the SCDs. They indicate presence of a permanent inflammatory process initiating at birth. The continuous inflammatory process alone causes an additional accelerated atherosclerotic process and a relative weight loss in the SCDs (31). Occlusions of vasculature of the bone marrow, bone infarctions, releasing of inflammatory mediators, and activation of afferent nerves may take a role in the pathophysiology of the intractable pains. Because of the severity of pain, narcotic analgesics are usually required to control them (32), but according to our practice, RBC supports are highly effective during severe crises both to relieve pain and to prevent sudden deaths secondary to the multiorgan failures developed on chronic inflammatory background of the SCDs.

Probably parallel to severity of the inflammatory process, an asplenism develops with decreased antibody production, prevented opsonization, and reticuloendothelial dysfunction due to the repeated infarctions and subsequent fibrosis in early years of life. Similarly, the prevalence of autosplenectomy was 51.6% (221 cases) among the patients with an average age of 30.3 ± 10.0 years (range 5-59), here. Terminal consequence of the asplenism is an increased risk of infections, particularly due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis like encapsulated bacteria. Thus, infections particularly the pneumococcal infections are common in early childhood, and they are associated with a high mortality rate. The causes of mortality were infections in 56% of infants in a previous study (29). In another study, the peak incidence of mortality occured between 1 to 3 years of age in children, and the deaths were predominantly caused by pneumococcal sepsis in patients less than 20 years of age (33). According to our nine-year experiences in adults, patients even who appear relatively fit are susceptible to sepsis, multiorgan failures, and sudden death during acute painful crises due to the deep immunosuppression in them.

ACS is responsible for considerable mortality, particularly during the childhood in the SCDs (34). It occurs most often as a single episode, and a past history is associated with an early mortality (34).

Similarly, all of 14 cases with the ACS had only a single episode, and two of them in the group without COPD were fatal in spite of rigorous RBC, ventilation, and antibiotic supports in the present study. The remaining 12 patients are still alive without a recurrence at the end of the nine-year follow-up period. ACS is the most common between the ages of 2 to 4 years, and its incidence decreases with age (35). Parallel to the knowledge, its incidence was only 3.2% among the patients with an average age of 30.3 years, here. The decreased incidence with aging may be due to a high mortality during the first episode and/or an acquired immunity against various antigens with aging. On the other hand, ACS may also show inborn severity of the SCDs. For example, its incidence is higher in severe cases such as cases with sickle cell anemia (HbSS) and a higher WBC count (34, 35).
Probably, ACS is a complex event, and the terminology of 'ACS' does not indicate a definite diagnosis but reflects clinical difficulty of defining a distinct etiology in the majority of such episodes. One of the major clinical problems lies in distinguishing between infection and infarction, and in establishing clinical significance of fat embolism. For example, ACS did not show an infectious etiology in 66% of episodes in the above studies (34, 35). Similarly, 12 of 27 episodes of ACS had evidence of fat embolism as the cause in another study (36). But according to our experiences, the increased metabolic rate during severe infections may terminate with the ACS. In other words, ACS may be characterized by the hard RBCs-induced disseminated endothelial damage and fat embolism at the capillary level. A preliminary result from the Multi-Institutional Study of Hydroxyurea in the SCDs (37) indicating a significant reduction of ACS episodes with hydroxyurea suggests that a substantial number of episodes are secondary to the endothelial inflammation and edema at the capillary level. Similarly, we strongly recommend hydroxyurea therapy for all patients at any age that may also be a cause of the low incidence of ACS among our follow-up cases, here. Hydroxyurea is the only drug that was approved by Food and Drug Administration for the treatment of SCDs (13). It is an oral, cheap, safe, and highly effective drug for the SCDs that blocks cell division by suppressing formation of deoxyribonucleotides which are building blocks of DNA (13). Its main action may be suppression of hyperproliferative WBCs and PLTs in the SCDs (14). Although presence of a continuous damage of hard RBCs on capillary endothelium, severity of the destructive process is probably exaggerated by the patients' own WBCs and PLTs as in the autoimmune disorders (14). Similarly, lower WBC counts were associated with lower crises rates, and if a tissue infarct occurs, lower WBC counts may decrease severity of pain and tissue damage (38). According to our experiences, hydroxyurea is an effective drug for prevention or delay of terminal consequences of the SCDs if it is initiated in early years of life, but it may be difficult due to the excessive fibrosis around the capillary walls in nearly all organs later in life.

As a conclusion, SCDs are chronic catastrophic processes on vascular endothelium particularly at the capillary level, and terminate with accelerated atherosclerosis induced end-organ failures in early years of life. RBC supports in severe clinical conditions probably prolong the survival of patients.