Original Article Autosplenectomy in Severity of Sickle Cell Diseases

Int J Clin Exp Med 2014;7(5):1404-1409 www.ijcem.com /ISSN:1940-5901/IJCEM0000171

Original Article Autosplenectomy in severity of sickle cell diseases

Mehmet Rami Helvaci, Can Acipayam, Ramazan Davran

Medical Faculty of The Mustafa Kemal University, Antakya Received March 6, 2014; Accepted May 9, 2014; Epub May 15, 2014; Published May 30, 2014

Abstract: Background: We tried to understand whether or not there is an association between prevalence of autosplenectomy and severity of sickle cell diseases (SCDs). Methods: All SCDs patients with red blood cell (RBC) transfusions of less than 50 units in their lives were put into the first group and 50 units or higher were put into the second group. Results: The study included 316 patients (155 females). There were 224 cases (70.8%) in the first group and 92 cases (29.1%) in the second group (p<0.001). The male ratio was significantly higher in the second group (64.1% versus 45.5%, p<0.001). Although both the white blood cell and platelet counts were higher in the second group, there was a significant difference in platelet counts (p=0.005), and this was probably due to the small sample sizes. Although the prevalence of autosplenectomy was significantly higher in the first group (56.2% versus 45.6%, p<0.05), the mean number of painful crises per year, digital clubbing, chronic obstructive pulmonary disease (COPD), leg ulcers, stroke, chronic renal disease (CRD) and coronary heart disease (CHD) were significantly higher in the second groups (p<0.05 for all). Conclusion: In contrast to the lower prevalence of autosplenectomy, the mean number of painful crises per year, digital clubbing, COPD, leg ulcers, stroke, CRD, and CHD were significantly higher in the second group. So there may be an inverse relationship between prevalence of autosplenectomy and severity of SCDs, and spleen may act as a chronic inflammatory focus as a filter of blood for these abnormally hard RBCs.

Keywords: Autosplenectomy, sickle cell diseases, chronic capillary damage

Introduction of their shapes is the major pathology of SCDs, since sickling is rare in the peripheric blood Probably systemic atherosclerosis is the main smears of patients with associated thalassemi- reason of aging by causing end-organ failures as, and the survival is not so affected in heredi- in human being. Although it mainly affects high tary elliptocytosis or hereditary spherocytosis blood pressure (BP) carrying arteries, the arte- as in the SCDs. Probably loss of elasticity sus- rioles and capillaries are probably affected with tains during the whole life, and exaggerate with some extent. Some of the triggering factors of various stresses. The hard RBCs can take their the systemic process are overweight, elevated normal elastic natures after normalization of BP, dyslipidemia, and insulin resistance for the the stressful conditions, but they getting hard development of terminal end points such as with time. The hard cells induced chronic capil- obesity, hypertension, diabetes mellitus (DM), lary damage, endothelial edema, and tissue peripheric artery disease, osteoporosis, chron- ischemia, and finaly leading to infarcts. On the ic obstructive pulmonary disease (COPD), other hand, obvious vascular occlusions may chronic renal disease (CRD), cirrhosis, coronary not develop in greater vasculature due to trans- heart disease (CHD), stroke, and aging, all of portation instead of their distribution functions which are collected in the metabolic syndrome for the hard RBCs. We tried to understand [1-6]. On the other hand, sickle cell diseases whether or not there is an association between (SCDs) are systemic capillary processes affect- ing whole systems of body which are caused by prevalence of autosplenectomy and severity of homozygous inheritance of hemoglobin S (Hb SCDs in the present study. S) [7, 8]. Hb S causes red blood cells (RBCs) to Material and methods loss their normal elastic and biconcave disc shaped structures under oxidative stresses. The study was performed in the Hematology Possibly loss of elasticity of the RBCs instead Service of the Mustafa Kemal University Autosplenectomy in sickle cell diseases

Table 1. Sickle cell patients with the red blood cell transfusions via MRI [11]. Autos- Cases with RBC* transfu- Cases with RBC transfu- plenectomy is diag- Variables p-value sions of less than 50 units sions of 50 units or higher nosed ultrasonogra- Prevalence 70.8% (224) <0.001 29.1% (92) phically in the ab- Mean RBC units 12.9 ± 11.2 (0-48) <0.000 99.0 ± 56.5 (50-362) sence of any history Mean age (year) 28.9 ± 9.9 (5-59) ns† 30.0 ± 9.2 (9-56) of splenectomy. CR- Male ratio 45.5% (102) <0.001 64.1% (59) D is diagnosed with a permanently ele- Thalassemia minors 62.0% (139) ns 58.6% (54) vated serum creati- Autosplenectomy 56.2% (126) <0.05 45.6% (42) nine level which is *Red blood cell. †Nonsignificant (p>0.05). 1.3 mg/dL or higher in males and 1.2 between March 2007 and February 2014. All mg/dL or higher in females on the silent phase. patients with SCDs were enrolled into the study. Cases with renal transplantation were put into SCDs are diagnosed by the hemoglobin electro- the CRD group. Cirrhosis is diagnosed with phoresis performed via high performance liq- hepatic function tests, ultrasonographic find- uid chromatography (HPLC). Their medical his- ings, ascites, and histologic procedure in case tories including numbers of painful crises per of requirement. Digital clubbing is diagnosed year, units of transfused RBC in their lives, with the ratio of distal phalangeal diameter to smoking habit, regular alcohol consumption, interphalangeal diameter which is greater than leg ulcers, stroke, and surgical operations were 1.0, and with the presence of Swamroth sign collected. Cases with a history of one pack-year [12, 13]. Associated thalassemia minors are were accepted as smokers, and cases with a detected by serum iron, total iron binding history of one drink a day for one year were capacity, serum ferritin, and the hemoglobin accepted as drinkers. A check up procedure electrophoresis performed via HPLC. A stress including serum iron, total iron binding capaci- electrocardiography is performed in cases with ty, serum ferritin, serum creatinine value on an abnormal electrocardiography and/or angi- three occasions, hepatic function tests, mark- na pectoris. A coronary angiography is obtained ers of hepatitis viruses A, B, and C and human just for the stress electrocardiography positive immunodeficiency virus, an electrocardiogra- cases. So CHD was diagnosed either angio- phy, a Doppler echocardiography both to evalu- graphically or with the Doppler echocardio- ate cardiac walls and valves, and to measure graphic findings as the movement disorders of the systolic BP of pulmonary artery, an abdomi- the cardiac walls. Eventually, cases with RBC nal ultrasonography, a Doppler ultrasonogra- transfusions of less than 50 units in their lives phy to evaluate the portal blood flow in required were put into the first and 50 units or higher cases, a computed tomography of brain, and a were put into the second groups, and the magnetic resonance imaging (MRI) of hips was groups were compared in between. Mann- performed. Other bone areas for avascular Whitney U test, Independent-Samples t test, necrosis were scanned according to the and comparison of proportions were used as patients’ complaints. Cases with acute painful the methods of statistical analyses. crises or any other inflammatory event were treated at first, and then the spirometric pulmo- Results nary function tests to diagnose COPD, the Doppler echocardiography to measure the sys- The study included 316 patients with SCDs tolic BP of pulmonary artery, peripheral blood (155 females and 161 males). There were 224 counts, renal and hepatic function tests, and cases (70.8%) in the first and 92 cases (29.1%) measurement of serum ferritin were performed in the second groups (p<0.001). There was a on the silent phase. The criterion for diagnosis nonsignificant difference according to the prev- of COPD is post-bronchodilator forced expirato- alence of associated thalassemia minors ry volume in 1 second/forced vital capacity of between the groups (Table 1). Mean ages of less than 70% [9]. Systolic BP of the pulmonary the groups were similar, too (28.9 and 30.0 artery of 40 mmHg or higher during the silent years, respectively, p>0.05). The mean units of phase is accepted as pulmonary hypertension transfused RBCs were 12.9 and 99.0, respec- [10]. A vascular necrosis of bones was detected tively (p<0.000). Interestingly, the male ratio

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Table 2. Sickle cell patients with peripheric blood values Cases with RBC* transfusions of less than Cases with RBC transfusions of 50 units or Variables p-value 50 units higher Mean WBC† counts (µL) 14.931 ± 6.791 (2.460-39.200) ns‡ 15.346 ± 5.640 (1.580-36.900) Mean PLT§ counts (µL) 435.670 ± 236.693 (48.000-1.827.000) 0.005 498.310 ± 224.570 (53.000-1.370.000) Mean hematocrit value (%) 23.8 ± 4.8 (11-42) ns 23.7 ± 4.9 (13-39) *Red blood cell. †White blood cell. ‡Nonsignificant (p>0.05). §Platelet.

Table 3. Clinical features of the sickle cell patients Cases with RBC* transfusions of Cases with RBC transfusions of Variables p-value less than 50 units 50 units or higher Painful crises per year 3.8 ± 6.3 (0-52) 0.000 8.4 ± 10.9 (0-52) Smoking 12.0% (27) ns† 17.3% (16) Digital clubbing 7.1% (16) <0.01 15.2% (14) Pulmonary hypertension 11.6% (26) ns 10.8% (10) COPD‡ 6.6% (15) <0.001 20.6% (19) Leg ulcers 11.6% (26) <0.01 21.7% (20) Stroke 5.8% (13) <0.05 11.9% (11) CRD§ 4.9% (11) <0.001 14.1% (13) Avascular necrosis of bones 20.5% (46) ns 17.3% (16) Cirrhosis 4.4% (10) ns 4.3% (4) CHD¶ 4.0% (9) <0.05 8.6% (8) Rheumatic heart disease 8.4% (19) ns 3.2% (3) Exitus 4.4% (10) ns 5.4% (5) *Red blood cell. †Nonsignificant (p>0.05). ‡Chronic obstructive pulmonary disease. §Chronic renal disease. ¶Coronary heart disease. was significantly higher in the second group was detected as negative by polymerase chain (45.5% versus 64.1%, p<0.001). Although both reaction in both. the white blood cell (WBC) and platelet (PLT) counts of the peripheric blood were higher in Discussion the second group, the difference was only sig- The SCDs mainly affect capillary endothelium nificant for the PLT counts (p=0.005), probably [14], since the capillary system is the main dis- due to the small sample sizes of the study tributor of the hard RBCs tissues. Due to the (Table 2). Mean hematocrit values were similar microvascular nature in microvascular compli- in the two groups (23.8% versus 23.7%, cations of DM, we can observe complete heal- p>0.05). In contrast to the significantly lower ing of leg ulcers with hydroxyurea therapy in prevalence of autosplenectomy, the mean early years of life, but the healing process may number of painful crises per year, digital club- be difficult due to the excessive fibrosis around bing, COPD, leg ulcers, stroke, CRD, and CHD the wounds later in life. Finally, the mean lifes- were significantly higher in the second group pan was 42 years in males and 48 years in (p<0.05 for all) (Table 3). Mean ages of the females in the literature [15], whereas it was mortal cases were 29.5 ± 9.8 (19-50) and 34.6 29 and 33 years in males and females in the ± 6.7 (26-44) years in the first and second present study, respectively. The great differ- groups, respectively (p>0.05). Mean ages of ences may be secondary to the initiation of the mortal cases were 29.7 ± 9.6 (19-50) and hydroxyurea therapy in early years of life in 33.3 ± 8.5 (21-44) years in males and females, developed countries. On the other hand, the respectively (p>0.05). On the other hand, there prolonged lifespan of females with SCDs and was no patient with regular alcohol consump- females in the world [16] can not only be tion among the study cases. Although antiHCV explained by the atherosclerotic effects of was positive in two of the cirrhotics, HCV RNA smoking alone, instead it may be explained by

1406 Int J Clin Exp Med 2014;7(5):1404-1409 Autosplenectomy in sickle cell diseases the dominant role of male sex in life [17]. in such patients in the present study. Similar to Similarly, the male ratio was significantly higher our results, increased WBC counts even in in the second and severe group in the present silent periods was an independent predictor of study (64.1% versus 45.5%, p<0.001). the disease severity [23], and it was associated with an increased risk of stroke by causing dis- The spleen is found in all vertebrates with a seminated capillary damage in brain [24]. Due similar structure to the lymph nodes. It acts pri- to the severity of pain, narcotic analgesics are marily as a blood fitler, which removes old and frequently required [25]. According to our prac- abnormal RBCs and recycles the iron. tice, simple and repeated RBC transfusions are Additionally, it synthesizes antibodies and highly effective both to relieve pain and to pre- removes antibody-coated bacteria and anti- vent sudden death which may develop second- body-coated blood cells from circulation. Like ary to the multiorgan failures on the chronic the thymus, the spleen has only efferent lym- inflammatory background. Simplicity of prepa- phatic vessels, and it is the major lymphatic ration of RBC suspensions in a short period of organ in the body. It has a central role in the time provides advantages to clinicians to use reticuloendothelial system, and it retains the them even in small public hospitals without the ability of producing lymphocytes after birth. need of specialized health workers and equip- The spleen acts as a pool of peripheral blood ments which are required for RBC exchange. cells and release the cells in case of require- Additionally, preparation of one or two units of ment. For example, it stores half of the body’s RBC suspension makes it possiable for clini- monocytes in mice [18]. When injured, the cians to prepare more units timely in case of monocytes can migrate to the injured tissue sudden death. By this way, deaths during trans- and transform into dendritic cells and macro- portation to some extent can be prevented. phages which assist tissue healing [19]. It was detected in the present study that 56.2% cases Hydroxyurea is a powerful drug for chronic of the first group and 45.6% of cases of the sec- myeloproliferative disorders and SCDs. It sup- ond group (p<0.05) had autosplenectomy, and presses cell division by blocking formation of these ratios were the highest ones compared deoxyribonucleotides which hampered the syn- with other affected tissues. So the spleen is thesis of DNA. So hydroxyurea primarily acts on probably the primarily affected organ in the hyperproliferative cells. Although the action body of such patients, and particularly due to way of hydroxyurea is thought to be the increas- the content of rich WBC, it may act as a chronic ing synthesis of gamma globin for fetal hemo- inflammatory focus. In the present study, a globin (Hb F) [26], its primary action may be the 28-year follow-up study of 740 veterans of suppression of hyperproliferative WBC and World War II with surgical removal of spleen PLTs in the SCDs. By this way, the continuous showed significant excesses of mortality inflammatory process of the SCDs that initiated caused by pneumonia and CHD [20], and the at birth on the capillary endothelium can be prevalence of CHD were significantly higher in suppressed to some extent. Due to the same the second group with lower prevalence of action way, hydroxyurea is also used to sup- autosplenectomy. press hyperproliferative skin cells in psoriasis. Although a continuous damage of hard cells Severe painful crises are nearly the pathogno- occurred in the capillary endothelium in the monic symptoms of the SCDs, and they are pre- SCDs, the severity of destructive process is cipitated by infection, operation, depression, or probably exaggerated by the patients’ WBCs injuries. Although the painful crises may not be and PLTs as in autoimmune diseases. So the thought as a directly life threatening [21], mechanism of -SCDs action in the body destruc- increased basal metabolic rate associated with tive process may mimic an autoimmune dis- the crises may terminate with multiorgan fail- ease. The suppression of excessive prolifera- ures on the chronic inflammatory background tion of patients’ WBC and PLTs by hydroxyurea of the SCDs [22]. The severe pain is probably may limit the capillary damage-induced tissue caused by the disseminated inflammation of ischemia and infarcts all over the body. the capillary endothelium, and the increased Similarly, lower neutrophil counts were associ- WBC and PLT counts and decreased hemato- ated with lower crises rates, and if a tissue crit values may indicate presence of a chronic infarction occurs, lower neutrophil counts may inflammatory process during whole their lives limit severity of pain and extent of tissue dam-

1407 Int J Clin Exp Med 2014;7(5):1404-1409 Autosplenectomy in sickle cell diseases age [27]. On the other hand, after the use of painful crises per year, digital clubbing, COPD, hydroxyurea, final Hb F levels did not differ from leg ulcers, stroke, CRD, and CHD were signifi- their pretreatment levels significantly [27]. cantly higher in the second group. So there may be an inverse relationship between prevalence Hydroxyurea may play a vital role in the SCDs of autosplenectomy and severity of SCDs, and [14]. The Multicenter Study of Hydroxyurea spleen may act as a chronic inflammatory focus studied 299 severely involved adults with sick- as a filter of blood for these abnormally hard le cell anemia (Hb SS), and compared the RBCs in the SCDs cases. results of patients treated with hydroxyurea or placebo [28]. The study particularly searched Disclosure of conflict of interest effects of hydroxyurea on painful crises, acute chest syndrome, and requirement of RBC trans- None. fusions. The results were so overwhelming in Address correspondence to: Mehmet Rami Helvaci, the favour of hydroxyurea that the study was Medical Faculty of The Mustafa Kemal University, terminated after 22 months, and hydroxyurea 31100, Serinyol, Antakya, Hatay, Turkey. Tel: 00-90- was initiated to all patients. The patients treat- 326-2291000 (3333); Fax: 00-90-326-2455654; ed with hydroxyurea had a 44% decrease of E-mail: [email protected] hospitalizations, and there was an independent association of lower neutrophil counts with the References lower crisis rates [28]. But this study was performed on severe Hb SS cases alone, and the [1] Eckel RH, Grundy SM, Zimmet PZ. The meta- frequency of painful crises was decreased from bolic syndrome. Lancet 2005; 365: 1415- 4.5 to 2.5 per year [28]. Whereas, we studied 1428. 337 patients with all subtype and severities of [2] Helvaci MR, Kaya H, Borazan A, Ozer C, Sey- the SCDs, and the frequency of painful crises hanli M, Yalcin A. Metformin and parameters of physical health. Intern Med 2008; 47: 697- was decreased from 10.3 to 1.7 per year 703. (p<0.000) with an additional decreased severi- [3] Helvaci MR, Kaya H, Seyhanli M, Yalcin A. ty (7.8 versus 2.2, p<0.000) in a previous study White coat hypertension in definition of meta- [29]. Parallel to the above, adult SCDs patients bolic syndrome. Int Heart J 2008; 49: 449- using the drug appear to have reduced mortal- 457. ity rate after a 9-year follow-up [30]. Although [4] Helvaci MR, Kaya H, Seyhanli M, Cosar E. the underlying disease severity remains vital to White coat hypertension is associated with a determine prognosis, hydroxyurea may decr- greater all-cause mortality. J Health Sci 2007; ease severity of disease [30] and prolong lifes- 53: 156-160. pan [14]. Chronic capillary damage is initiated [5] Helvaci MR, Aydin LY, Aydin Y. Chronic obstruc- at birth, and complications initiate to be seen in tive pulmonary disease may be one of the terminal end points of metabolic syndrome. Pak J infancy. For instance, infants with lower hemo- Med Sci 2012; 28: 376-379. globin levels, as an indicator of chronic inflam- [6] Stojanovic OI, Lazovic M, Lazovic M, Vuceljic M. matory process, were more likely to have higher Association between atherosclerosis and os- incidences of acute chest syndrome, painful teoporosis, the role of vitamin D. Arch Med Sci crises, and lower neuropsychological scores, 2011; 7: 179-188. and hydroxyurea reduced the incidences of [7] Helvaci MR, Erden ES, Aydin LY. Atherosclerotic them [31]. Hydroxyurea initiated in early years background of chronic obstructive pulmonary of life may protect splenic function, improve disease in sickle cell patients. HealthMed growth, and prevent multiorgan dysfunctions 2013; 7: 484-488. by preventing chronic capillary damage. [8] Helvaci MR, Aydin Y, Ayyildiz O. Clinical severity Transfusion programmes also reduce these of sickle cell anemia alone and sickle cell diseases with thalassemias. HealthMed 2013; 7: complications, but they carry some significant 2028-2033. risks including infections, development of allo- [9] Global strategy for the diagnosis, management antibodies, and iron overload. Additionally, and prevention of chronic obstructive pulmo- using a drug orally is a much more easier meth- nary disease 2010. Global initiative for chronic od than regular transfusions for the patients, obstructive lung disease (GOLD). for their families, and for the health systems. [10] Fisher MR, Forfia PR, Chamera E, Housten- Harris T, Champion HC, Girgis RE, Corretti MC, As a conclusion, in contrast to the lower preva- Hassoun PM. Accuracy of Doppler echocar- lence of autosplenectomy, the mean number of diography in the hemodynamic assessment of

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