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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 14  |  Issue : 2  |  Page : 57-77

A compendium of pathophysiologic basis of etiologic risk factors for painful vaso-occlusive crisis in sickle cell disease


1 Department of Hematology, Aminu Kano Teaching Hospital, Kano, Kano State, Nigeria
2 Department of Pediatrics, Aminu Kano Teaching Hospital, Kano, Kano State, Nigeria

Date of Web Publication5-Oct-2017

Correspondence Address:
Sagir G Ahmed
Department of Hematology, Aminu Kano Teaching Hospital, PMB 3452, Kano, Kano State
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njbcs.njbcs_11_17

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  Abstract 

Sickle cell disease (SCD) is characterized by recurrent vaso-occlusive crisis (VOC). VOC is an important index of disease severity and has been shown to correlate with the risk of multi-organ damage and early death. Although the vulnerability to VOC among patients with SCD may be genetically predetermined on the basis of genotype and haplotype variability, nonetheless, VOC is usually triggered by a wide spectrum of etiologic risk factors, which range from physiological to nonphysiological factors on the one hand, and from psychological to physical factors on the other hand. An understanding of these risk factors and their pathophysiologic mechanisms is important for the hematologist to accurately identify potential etiologic risk factors for VOC. Thus taking preemptive action that will prevent undue exposure of patients to the risk factors and/or prepare the patient to uneventfully withstand the risk factors if exposure is unavoidable. This will ultimately obviate frequent VOC with its attendant risk of organ damage and early death in patients with SCD. Hence, in this study we conducted a broad and comprehensive review (using “sickle cell painful vaso-occlusive crisis” and relevant sub-terms in PubMed, Google Scholar, and other search engines) of various etiologic risk factors for VOC and the pathophysiologic mechanisms through which they trigger pain in patients with SCD.

Keywords: Pathophysiology, risk factors, sickle cell, vaso-occlusive crisis


How to cite this article:
Ahmed SG, Ibrahim UA. A compendium of pathophysiologic basis of etiologic risk factors for painful vaso-occlusive crisis in sickle cell disease. Niger J Basic Clin Sci 2017;14:57-77

How to cite this URL:
Ahmed SG, Ibrahim UA. A compendium of pathophysiologic basis of etiologic risk factors for painful vaso-occlusive crisis in sickle cell disease. Niger J Basic Clin Sci [serial online] 2017 [cited 2017 Dec 18];14:57-77. Available from: http://www.njbcs.net/text.asp?2017/14/2/57/216045


  Introduction Top


Hemoglobin S (HbS) is a structural variant of normal hemoglobin (HbA). HbS arose as a consequence of genetic mutation in the normal β-globin gene within which thymidine replaced adenine, thus resulting in the substitution of glutamic acid by valine at position 6 of the β-globin chain.[1] This substitution caused a significant change in the physicochemical properties of HbS, which has a reduced solubility in the deoxygenated state.[2] The sickle β-gene mutation confers relative protection against falciparum malaria among individuals with sickle cell trait (SCT).[3] Consequently, children with SCT have relatively higher survival advantage in malaria endemic regions of the world.[3] This situation is responsible for the high prevalence of SCT in the malaria endemic regions of Africa where up to 10–40% of local populations carry the trait.[3] Hence, malaria infection is the single-most important agent for the perpetuation of SCT that has led to propagation and a high prevalence of sickle cell disease (SCD) in black Africa.[3] The sickle cell anemia (SCA), which is the homozygous inheritance of HbS gene, is the prototype and most common type of SCD, but less common types of SCD also arise as a result of double heterozygosity between HbS gene and different β-globin gene mutations such as hemoglobin C (HbSC) or β-thalassemia (HbSβthal), which share a similar basic pathophysiology of red cell sickling, tissue infarction, and vaso-occlusive crisis (VOC).[2] The clinical presentation of SCD is dominated by vaso-occlusive episodes resulting from polymerization of deoxygenated HbS and the formation of sickled red cells.[2] The clinical course of SCD is typically characterized by variable periods of painless steady state that is sporadically interrupted by painful VOC.[4]

VOC is an important index of disease severity in SCD.[5] The severity and frequency of VOC in SCD has been linked to several genetic factors, including the disease genotypes and β-globin gene haplotypes. The non-HbSS genotypes such as HbSC and HbSβthal are associated with lower blood HbS proportions and/or lower mean corpuscular hemoglobin concentration (MCHC), less frequent VOC, and milder disease.[4] The Saudi and Senegal haplotypes are associated with higher HbF levels, less frequent VOC, and milder disease, while the Benin, Bantu, and Cameroon haplotypes are associated with lower HbF levels, more frequent VOC, and severer disease.[6] Genetic variations outside the β-globin gene cluster may also modify the vulnerability of SCD patients to VOC. Some studies have shown that coinheritance of G-6-PD deficiency in SCD patients may increase background hemolysis and reduce steady-state hematocrit, resulting in lower blood viscosity with less frequent VOC,[7] which clinically simulates the hemolytic phenotype. In addition, other studies have shown that because of the important role of von Willebrand factor (vWF) as a mediator of cellular adhesion in the pathophysiology of VOC [8],[9] and a determinant of SCD severity,[10] SCD patients with non-O blood group have higher risk of VOC in comparison with their counterparts with blood group O in whom vWF levels are relatively lower.[11] It, therefore, appears that the vulnerability to VOC among SCD patients may have been genetically predetermined on the basis of genotype [4] and haplotype [6] variations in the β-globin gene cluster, as well as variations in some non-β-globin genes such as the G-6-PD [7] and ABO blood group [11] genes. Nonetheless, VOC is usually triggered by a wide spectrum of nongenetic etiological risk factors, which range from physiological to nonphysiological factors on the one hand, and from psychological to physical factors on the other hand.

The frequency of VOC has been shown to correlate with the risk of multiorgan damage and early deaths among patients with SCD.[4] Moreover, frequent VOC is associated with frequent consumption of nonsteroidal antiinflammatory analgesics that increase the risks of peptic ulceration [12] and nephropathy,[13] while frequent consumption of narcotic analgesics may increase the risk of opiate dependence [14] among SCD patients. It is, therefore, important for hematologist to comprehensively understand the extent of all clinically significant risk factors for VOC and the pathophysiologic mechanisms through which they trigger pain in patients with SCD. A thorough understanding of these risk factors and their pathophysiologic mechanisms will help the hematologist to accurately identify potential etiologic risk factors for VOC and take preemptive action that will prevent subsequent patient exposure to the risk factors and/or prepare the patient to uneventfully withstand the risk factors if subsequent exposure is unavoidable. This strategy will decrease the frequency of VOC, minimize the adverse effects of analgesic drug use, and reduce the overall risk of multiorgan damage and early death. Hence, this study conducted a broadly and comprehensive review of various etiologic risk factors for VOC and the pathophysiologic mechanisms through which they trigger pain in patients with SCD, as outlined in [Table 1].
Table 1: Risk factors and pathophysiology of sickle cell VOC

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  Idiopathic or Spontaneous: No Obvious Risk Factors Top


Sickle cell VOC is usually triggered by clinically discernible etiological risk factors in the majority of cases. However, in minority of cases there may be no obvious clinical or laboratory evidence of physiological or nonphysiological precipitating risk factors for the VOC. Such apparent cases of “idiopathic” or “spontaneous” VOC may in reality be due to subtle psychological factors to which the patients/parents themselves are oblivious. Hence, all cases of apparently “spontaneous” VOC, especially in recurrent cases, should carefully be evaluated for possible underlying psychological causes.


  Physiological Risk Factors Top


Menstruation and pregnancy are important physiological factors that are known to be associated with a number of physical and psychological changes capable of precipitating VOC in patients with SCD.

Menstruation

Menstruation-induced vaso-occlusive crisis (MIVOC) has not been extensively studied. Yet it is an important cause of pain in many young women with SCD. The possible pathophysiologic mechanisms of MIVOC can be reviewed from gynecological, hematological, hormonal, and psychological perspectives.

Gynecological and hematological profiles of patients with SCD and MIVOC

Some studies had pointed to the onset of menstruation as a possible precipitant of painful VOC in some women with SCD.[15],[16],[17] A prospective observational study in women with SCD revealed normal mean cycle lengths with normal duration and rate of menstrual blood flow.[15] Nonetheless, more than half of the women studied had some form of cyclical VOC in association with their menstrual cycles.[15] This report suggests that MIVOC is not uncommon among female patients with SCD. However, another prospective cohort study reported that female patients with SCD who had MIVOC were significantly older and had longer and heavier menstrual periods,[16] which would suggest that the advancing age and intensity of menstrual blood loss may increase the risk of MIVOC. Yet another prospective cohort study revealed that patients with SCD and MIVOC had normal menstrual cycle but had a significant elevation of platelet count during menstruation, which was thought to denote an exaggerated reactive thrombocytosis triggered by normal menstrual blood loss.[17] The study concluded that intramenstrual elevation of platelet count seen among patients with MIVOC could have elevated the patients' whole-blood viscosity and platelet reactivity, which consequently triggered the painful vaso-occlusive episodes.[17] Hence, it was hypothesized that patients with MIVOC in association with intense thrombocytosis may benefit from low-dose aspirin therapy that may potentially abolish or reduce the intensity of the crisis.[17]

Hormonal impact on SCD red cell deformability, aggregability, and sicklability: Possible role in MIVOC

Previous studies had focused on the possible roles of hormonal factors in the pathogenesis of VOC.In vitro studies had revealed that both estradiol and progesterone showed low affinity binding to HbSS erythrocytes but did not affect deformability,[18] sicklability,[19] or osmotic fragility [19] of the erythrocytes. Nonetheless, another in vitro study had demonstrated that β-estradiol significantly decreased erythrocyte aggregation and reduced blood viscosity in the blood of non-SCD postmenopausal women undergoing hormone therapy.[20] Based on the result of this study,[20] we are inclined to believe that the physiological drop in the level of estrogen that occurs during menstruation [21] would have the opposite effect of enhancing red cell aggregability and aggravating blood viscosity, which could trigger MIVOC since elevations in red cell aggregability and blood viscosity are well-known triggers of VOC, as clinically exemplified in patients with SCD comorbid multiple myeloma.[22] In addition, other studies had shown that estrogens significantly decrease hypoxia-induced erythropoietin production [23] and inhibit erythropoiesis.[24] It is, therefore, possible that the drop in estrogen level during menstruation [21] would lead to greater erythropoietin production [23] and increased erythropoiesis.[24] Hence, we speculate that the menstrual period may be associated with a greater marrow hyperplasia, which would lead to marrow hypoxia with increased risk of intramedullary red cell sickling, marrow infarction, and VOC. Moreover, estrogen has been shown to induce vasodilatation, while progestin has more variable bidirectional vasoregulatory effects on arterial tone through their ability to induce both vasodilatation and vasoconstriction depending on physiological needs.[25] So, it can be speculated that the physiologically low levels of ovarian hormones that occur during menstruation [21] probably predispose to MIVOC by downregulating hormonally mediated red cell disaggregation [20] and vasodilatation [25] in patients with SCD. It is, therefore, not surprising that a previous study had revealed that the use of hormonal contraception in the form of low dose combined oral pills (containing both estrogen and progesterone) or Depo-Provera (progesterone-only long-acting injection) were associated with significant reduction in the overall frequency of VOC in female patients with SCD.[26] Moreover, injectable progesterone preparations such as Depo-Provera are known to have red cell membrane stabilizing effect that can reduce the frequency of VOC in patients with SCD.[27] Thus, Depo-Provera injection may be considered a possible option in preventing MIVOC in female patients with SCD who are not desirous of pregnancy. Depo-Provera would confer double advantage in such cases because it would induce amenorrhea and consequently completely abolish MIVOC with an added advantage of significantly reducing the overall frequency of nonmenstruation-induced VOC as previously reported.[26] The aforementioned speculations and presumptions obviously call for more definitive studies on the interrelationship between ovarian hormones, red cell sickling, and induction of MIVOC.

Psychological perspectives of menstruation: Possible role in MIVOC

In some women, hormonal fluctuations during the menstrual cycle are regularly associated with the development of premenstrual syndrome (PMS), which is characterized by abnormal physical, behavioral, and psychological symptoms that usually begin in the second half of the cycle, and are significantly improved or resolved by the end of menstruation.[28] The psychological symptoms may include mood swings, depression, anxiety, and irritability.[28] Therefore, there is the need to investigate whether PMS is a risk factor for MIVOC in female patients with SCD because of the well-established roles of psychological and mood disorders in the pathogenesis of sickle cell VOC.[29],[30]

Pregnancy: Plasma and cellular changes, immune modulation

VOC occurs more often in pregnancy and is one of the most common maternal complications associated with SCD. Pregnant women with SCD can develop VOC in the antepartum, intrapartum, and postpartum periods. However, painful crises are more common with advancing pregnancy and in the postpartum period.[31] Many of the hormonal and physiological changes that are associated with normal pregnancy can potentiate the basic pathophysiology of red cell sickling and increase the frequency of VOC in the pregnant mother with SCD. These pregnancy-associated changes include placental G-cerebrospinal fluid (G-CSF)-induced neutrophilia,[32] increased levels of most pro-coagulant factors including vWF,[33] hyperfibrinogenemia with increased plasma viscosity,[34] and increased red cell aggregability,[35] as well as increased plasma levels of placental angiogenic growth factor,[36] all of which are known to contribute adversely to the pathophysiology, risk, and frequency of VOC as previously reported in patients with SCD.[22],[37],[38],[39] Moreover, the majority of patients with SCD live in tropical countries with heavy burden of infectious diseases. The immune modulation effect of pregnancy increases the risk of acquiring locally ubiquitous bacterial [40] and parasitic infections,[41] which will greatly increase the risk and frequency of VOC in pregnant women with SCD living in the tropics.[42] Clinicians should also anticipate that preconception suspension of hydroxyurea therapy may decrease HbF levels and de-repress endothelial angiogenic mechanisms [43] with a resultant rebound increase in the frequency of VOC in pregnant patients with SCD who were previously taking hydroxyurea during the prepregnant period. Pregnancy-associated VOC should be treated adequately but cautiously because of the potential adverse effects of pain-relieving drugs on the fetus. Maternal use of narcotic analgesics may cause respiratory depression and neonatal abstinence syndrome shortly after birth, while nonsteroidal antiinflammatory drugs (NSAIDs) should be generally avoided after 30 weeks of gestation because of the risk of premature narrowing or closure of fetal ductus arteriosus that would cause severe cardiovascular instability in the newborn.[31] Blood transfusion therapy is not routinely recommended in the management of VOC in pregnancy. However, in pregnant patients with recurrent severe VOC, the risk to benefit ratio of prophylactic exchange blood transfusion should be carefully considered on the basis of individual patients' clinical and obstetric history, and/or the presence of compounding comorbidities.[44]


  Nonphysiological Risk Factors Top


Nonphysiological etiologic risk factors for sickle cell VOC range from mental to physical disorders that are capable of directly or indirectly causing significant augmentation of the pathophysiologic pathways for VOC.

Mental stress, anxiety, and depression

Psychological disorders including mental stress, anxiety, and depression are common comorbidities among patients with chronic medical diseases including SCD.[45] Moreover, there is a reciprocal bidirectional relationship between psychological disorders and VOC in patients with SCD.[29],[30] While painful stress due to recurrent VOC can lead to the development of psychological disorders,[29] psychological disorders can also increase the frequency of VOC in patients with SCD,[30] thus creating an undesirable noxious vicious cycle that can disrupt the physical and psychological well-being of these patients.

Psychological disorders are often associated with the release of a number of stress-related hormones such as catecholamines and corticosteroids.[46] These stress hormones have the potential to increase the risk of sickle cell VOC by adversely affecting blood cell count, plasma volume, and blood viscosity. Corticosteroids [47] and catecholamines [48] are hormonal mediators of stress neutrophilia that will enhance neutrophil-endothelial adhesion, which is an important risk factor for VOC in patients with SCD.[37] In addition, the pain and anxiety associated with sickle cell VOC may lead to a very brisk release of catecholamines, which could induce moderately intense transient stress lymphocytosis [49] that would aggravate blood viscosity and perpetuate the crisis.[50] Moreover, results from previous studies have suggested that corticosteroids may act directly on smooth muscles of blood vessels, thereby potentiating the vasoconstrictor actions of catecholamines,[51] a situation that may aggravate the risk of tissue hypoxia, red cell sickling, and VOC in patients with SCD. A previous study on reactivity of blood cells of individuals with SCT revealed a significant upregulation of BCAM/Lu and ICAM-4 expression with increased frequency and strength of adhesion events after exposure to epinephrine.[52] This study highlights the adverse potential effects of catecholamines in triggering VOC in patients with SCD during psychological stress. In addition, prolonged psychological stress can lead to a significant reduction in plasma volume with concomitant hyperproteinemia and rise in whole blood and plasma density,[53] all of which will jeopardize tissue perfusion and ultimately predispose to sickle cell VOC.[50] Prolonged psychological stress is by itself associated with immunosuppression,[54] which would aggravate the preexisting SCD associated immunosuppression and predispose to more infections and frequent VOC.[42] Suffices to note that depression and anxiety are also known to be associated with reduced pain threshold coupled with heightened pain perception and reporting,[55] which may lead to increased emergency hospital visits for pain episodes that would otherwise be perceived as trivial by patients with SCD without depression and/or anxiety. It is, therefore, recommended that these patients who present with recurrent frequent VOC devoid of discernible physical precipitating factors should be carefully evaluated for underlying comorbid psychological disorders. Appropriate treatment modalities, which may include counseling, anxiolytics, or antidepressants, will surely reduce the frequency of VOC in patients with SCD with comorbid psychological disorders.

Physical stress and exercise

The stress induced by physical exercise causes significant alterations in oxygen consumptions, tissue metabolism, production of biochemical waste, autonomic equilibrium, and cardiovascular functions. The concert between these changes can predispose to the development of sickle cell VOC. However, the outcome of physical exercise in patients with SCD is to a large extent determined by the intensity of the exercise.

Metabolic and biochemical changes

Vigorous exercise and physical activity generally increase oxygen consumption and glucose utilization in the tissues.[56] Consequently, exercise is known to induce marked metabolic and biochemical changes in the body, including lactic acidosis, tissue hypoxia, increased body temperature, dehydration, and increased blood viscosity, all of which predispose toward HbS polymerization, red cell sickling, microvascular occlusion, and VOC in patients with SCD.[56],[57],[58] The deleterious effect of vigorous exercise is not limited to patients with SCD as it has been reported that vigorous exercise can produce adverse consequences even in apparently healthy persons with SCT. A previous study had reported that tissue hypoxia and lactic acidosis associated with vigorous physical exercise in previously healthy athletes with SCT were responsible for inducing red cell sickling resulting in fatal ischemic rhabdomyolysis and renal failure.[59] Moreover, analysis of data derived from the National Collegiate Athletic Association of the USA revealed that the risk of exertional death was several times higher in football athletes with SCT than in those without SCT.[60] However, whether or not prospective (non-White) athletes in the USA or anywhere else in the world should be screened for SCT remains an area of racially sensitive deliberations.

Autonomic nervous system disequilibrium

Apart from metabolic and biochemical changes, vigorous exercise can also induce autonomic changes that can independently precipitate VOC in patients with SCD. Animal experimental evidences suggest that chronic hypoxia causes cell loss in the nucleus ambiguous from which several vagal efferent axons originate,[61] a situation that is thought to be responsible for parasympathetic withdrawal and sympathetic predominance in patients with SCD.[62] This autonomic disequilibrium is to a lesser extent also seen in apparently healthy asymptomatic subjects with SCT,[63] in whom it may also be attributed to chronic subclinical sickling with subtle hypoxic injury in the central nervous system (CNS). Autonomic disequilibrium confers upon patients with SCD an abnormal baseline autonomic sympatho-vagal imbalance with elevated peripheral vasoconstrictor tone, which can precipitate or exacerbate VOC.[64] The degree of parasympathetic withdrawal correlates with disease severity in SCD.[64] Patients with SCD with larger parasympathetic withdrawal generally have severer disease with more frequent VOC, while relatively smaller parasympathetic withdrawal is usually associated with less severe disease and infrequent VOC.[64] In healthy individuals, a single intense exercise session can significantly alter the autonomic tone toward sympathetic predominance that is well tolerated.[65] However, vigorous exercises must be avoided in patients with SCD in whom further pro-sympathetic autonomic alteration is undesirable and intolerable as it will cause greater peripheral vasoconstriction and trigger frequent VOC.[64]

Tolerance and possible benefits of mild–moderate physical exercise in SCD

Despite the deleterious effects of vigorous exercise, mild to moderate exercise was found to be safe in SCD as it did not cause significant alterations in autonomic tone or trigger VOC in a controlled study conducted among patients with SCD.[66] However, some studies have demonstrated that although mild to moderate exercise is usually well tolerated by patients with SCD without VOC or any acute clinical complications, care should be taken because markers of oxidative stress and endothelial activation were significantly increased in some patients.[67] Interestingly, some studies have reported that moderate physical exercise in patients with SCD resulted in postexercise improvement in red cell aggregation indices that will improve microcirculatory blood flow and mitigate the occurrence of VOC.[68] Hence, mild to moderate exercise is not contraindicated in SCD and may in fact be beneficial if carefully monitored. But prescribing and administering the correct intensity of exercise without overshooting the mild to moderate range may be difficult and requires expertise. Mild to moderate exercise roughly corresponds to about 36–50 Watts output, which is equivalent to the daily amount of physical activity that is required to go to work, climb the staircase, and do routine shopping.[69] However, patients with SCD must maintain adequate fluid intake throughout the period of exercise even if conducted in the mild to moderate range. Nonetheless, some studies have revealed that even moderate exercise can induce significant postexercise and nocturnal hypoxia with real risk of triggering VOC, particularly in children and adolescents with SCD [70] in whom only milder exercise may be administered with caution.

Topography, weather, and climatic factors

Geographical factors and weather elements have significant impact on the pathophysiology and frequency of sickle cell VOC. Many studies have demonstrated definite associations between frequency of VOC and variations in many atmospheric conditions.

High ambient temperature, evaporation, dehydration

The majority of patients with SCD live in hot tropical countries of the world.[1] With the largest back population of over 170 million, SCT frequency of 25–30%, and SCD prevalence of 1–3%, Nigeria carries the heaviest burden of SCD in the world.[71] A previous study had revealed an increased frequency of sickle cell VOC in the middle of the non-Harmattan dry season, which is associated with the most intensely hot temperatures of the calendar year in northern Nigeria.[72] The pathophysiologic basis of the rise in frequency of VOC during the period of hot ambient temperature was thought to be associated with excessive sweating and high rate of insensible water loss resulting in dehydration, which would invariably cause an increased plasma osmolality, hemoconcentration, microvascular stasis, and raised erythrocyte MCHC. The hemorheological and hemodynamic consequences of these changes would lead to increased HbS deoxygenation, gelation, and polymerization, all of which will culminate in enhanced red cell sickling and VOC in patients with SCD.[50],[73] Furthermore, it should be appreciated that patients with SCD are particularly vulnerable to dehydration because the disease is often associated with recurrent renal papillary necrosis, impairment of renal water re-absorption, and hyposthenuria,[74] which will invariably aggravate body water deficit due to excessive sweating and insensible water loss during hot seasons. This vulnerability underscores the need for liberal oral fluid intake by patients with SCD during hot weather in order to attenuate the vicious pathophysiologic cascade of dehydration, hyperviscosity, and VOC.

Low ambient temperature, wind speed, skin cooling

SCD is predominantly tropical in its distribution. However, increasing number of individuals with SCD that are currently living in colder temperate regions of the world as a result of inter-regional migrations attributable to political upheavals, wars, socioeconomic instability, and educational pursuits. Previous studies have implicated skin cooling due to direct effect of low ambient temperatures or due to rapid evaporation of skin moisture resulting from the effect of high winds of low humidity as triggers of VOC in patients with SCD.[75],[76] The pathophysiology of VOC following cold exposure is related to an interplay between effect of temperature on HbS polymerization, vasoconstriction, stasis, red cell sickling, and water loss due to cold-induced diuresis. Paradoxically, it is a well-known fact that cold temperatures decrease the rate of HbS polymerization,[73] and by inference, low temperatures should beneficially reduce the occurrence of VOC. This expected beneficial inhibitory effect of cold on HbS polymerization is apparently counterbalanced by the adverse effect of cold-induced exaggerated reflex peripheral vasoconstriction,[75],[77] which causes relative stasis and greater deoxygenation of peripheral blood resulting in increased production and accumulation of circulating sickled red cells that subsequently cause VOC.[78] In addition to peripheral vasoconstriction, another mechanism underlying the pathogenesis of cold-induced VOC in SCD is probably related to abnormal neurovascular reflexes leading to deeper intramedullary vasoconstriction, hypoxia, and marrow infarcts resulting in VOC based on the concept of the “steal” syndrome hypothesis.[79] Direct contact between body parts and ice can trigger intense vasoconstriction with a high risk of developing gangrene that may even lead to amputation.[80] Exposure to cold temperatures is also known to inhibit the release of antidiuretic hormone (ADH), suppress renal ADH receptor, and reduce renal re-absorption of water,[81] a situation that may increase blood viscosity and predispose to red cell sickling and VOC in patients with SCD.[50] It can be speculated that the increase in frequency of VOC during cold seasons may be related to seasonal increase in the rates of respiratory tract infections during winter.[82] Nonetheless, a previous study had shown that even when VOC cases with overt infections were excluded, the cold winter months were associated with increased rates of VOC that were attributed to increased blood viscosity resulting from cold-induced diuresis.[82] Moreover, seasonal variations in cortisol levels showed higher figures during the cold winter months,[83] a situation that may predispose to frequent VOC in patients with SCD because of the well-known role of corticosteroids in triggering VOC.[84] It is, therefore, important that these patients should be adequately protected from excessive cold and winds in order to mitigate the deleterious effect of these weather elements on the frequency of VOC.

Tropical rainy season, humidity, mosquitoes, malaria transmission

Previous studies relating to the effects of humidity on sickle cell VOC have produced discordant results. While some studies have reported higher pain scores in more humid months of the year,[85] other studies suggested that lower humidity was associated with more VOC,[76] and yet a more recent study found that both high and low humidity conditions were associated with increased frequent VOC.[86] Unlike the temperate countries, the tropical countries within which the majority of patients with SCD live, usually have distinct dry and rainy seasons. In a Nigerian study, the tropical rainy season has been shown to be associated with increased frequency of sickle cell VOC.[72] The rise in frequency of VOC during the tropical rainy season was thought to be two-fold. First, the rainy season is normally associated with rising atmospheric moisture and humidity, which is an important risk factor for frequent VOC in patients with SCD.[85] Second, the tropical rainy season is associated with increased availability of stagnant surface waters with resultant increase in agricultural and nonagricultural vegetations, all of which are ideal for reproduction and survival of mosquito vectors for the malaria parasites.[87] Consequently, the tropical rainy season is a period of intensive transmission of malaria infection,[88] which is reported to be the commonest cause of VOC in patients with SCD living in tropical countries such as Nigeria.[89] Although it is difficult to control local humidity, it is, nonetheless, possible to reduce the risk of VOC by stricter application of preventive measures such as the use of insecticide-treated bed nets and regular administration of antimalarial chemo-prophylactic drugs in order to reduce the incidence of VOC during high-risk periods such as the tropical rainy seasons.[90]

High altitude, low atmospheric oxygen, hypoxia

Ascending to high altitudes is potentially dangerous for patients with SCD due to the fact that partial pressure of atmospheric oxygen steadily falls with rising altitude.[91] Significant fall in partial pressure may in the short term aggravate hypoxia, induce acute red cell sickling, and predispose to acute VOC or splenic infarcts, which has been reported in SCT [92] as well as in SCD.[93] Long-term continuing hypoxia would increase erythropoietin production [94] with a concomitant rise in steady-state hematocrit, which would raise blood viscosity and predispose to more frequent VOC.[50] A classical example of this scenario is demonstrated in a Saudi Arabian study, which found that the level of steady-state hemoglobin and the rate of acute vaso-occlusive complications in patients with SCD living in the highlands were significantly higher than that of their counterparts living on low lands.[95] The theoretical risk of developing acute vaso-occlusive complications by steady-state patients with SCD when flying in well-pressurized commercial aircrafts is small. Nonetheless, preflight exchange transfusions or even in-flight oxygen supplementation may be recommended for critically sick and nonsteady-state patients with SCD if the flight is unavoidable.

Infections: Immunosuppression and susceptibility to microbial agents

The vast majority of patients with SCD live in poor tropical countries with high infectious disease burden. Patients with SCD have increased susceptibility to infections due to a range of immune-related abnormalities, including autosplenectomy resulting from recurrent vaso-occlusive splenic infarcts, as well as abnormalities of antibody production, the alternate complement pathway, opsonization, leukocyte functions, and cell-mediated immunity.[96] The range of immune abnormalities largely determines the pattern of microbiological susceptibility. Autosplenectomy and hyposplenism predisposes to severe infections with Malaria and Babesia species as well as encapsulated organisms, including Hemophilus influenza and Streptococcus pneumoniae, while low serum immunoglobulin M (IgM) levels, impaired opsonization, and abnormality of complement pathway increase susceptibility to other infectious agents, including Mycoplasma pneumoniae, Salmonella typhimurium, Staphylococcus aureus, and Escherichia coli.[96] Another factor that increases the susceptibility of patients with SCD to infection is chronic transfusion therapy, which can cause iron overload and raise the risk of infections with iron-dependent bacteria such as Yersinia species.[97] Chronic blood transfusion can also predispose these patients to infections by inducing immune modulation and suppression,[98] and by direct inoculation with intraerythrocytic transfusion transmissible parasites and bacteria such as Malaria,[99] Babesia,[100] and Bartonella species.[101] Bacterial and parasitic infections can induce a myriad of pathophysiologic changes that can predispose to VOC in patients with SCD.

Pulmonary infection and inflammation: Impaired gaseous exchange, hypoxia

The respiratory tract is a common site of acute and chronic infections by both typical and atypical pathogens that are capable of precipitating VOC.[42] Acute bacterial pneumonia due to community-acquired pathogens may incite intense pneumonic inflammatory response and rapidly progress to acute chest syndrome (ACS).[102] Severe acute bacterial pneumonia with or without ACS may be associated with intense alveolar consolidation and pulmonary sequestration of sickled red cells, resulting in lung tissue injury and impaired gaseous exchange across the alveolar membrane.[102] These pulmonary changes would predictably lead to generalized hypoxia, increased red cell sickling, and VOC. Chronic chest infections, such as pulmonary tuberculosis, can also interfere with pulmonary function and increase the risk of red cell sickling and VOC in patients with SCD.[103] The most important atypical causative agent of pneumonia and ACS in patients with SCD is Mycoplasma pneumoniae, which is particularly common in young children.[104] Mycoplasma infection can be complicated by the development of cold [105] or rarely warm [106] reacting red cell autoantibodies that can cause agglutination and hemolysis. Therefore, Mycoplasma infection is particularly hazardous in patients with SCD because apart from its associated risk of pneumonitis and ACS, the infection can also aggravate hemolysis and induce red cell agglutination, both of which will predispose to VOC by raising plasma-free heme [107] and increasing blood viscosity,[50] respectively. Therefore, in addition to antibiotic therapy, patients with SCD, chest infection, and/or ACS must be closely monitored by blood gas analysis and managed with oxygen supplementation and/or exchange blood transfusion as dictated by the degree of hypoxia and any superimposed VOC. In addition to antibiotic prophylaxis,[108] respiratory tract infection and sepsis in SCD can be significantly reduced in incidence and severity with the use of polyvalent pneumococcal [109] and Hemophilus influenzae type-b [110] vaccines during early childhood.

Plasma acute phase reaction: Oxidative stress, hypercoagulability, and hyperviscosity

Vaso-occlusive tissue necrosis, though more pronounced during VOC, also occur at lower rate during the steady state.[111] Re-perfusion of necrotic tissues generates oxygen radicals and inflammatory tissue injury.[112] Hence, many inflammatory markers of acute phase reaction, including C-reactive protein, tumor necrosis factor (TNF)-α, interleukin-1 and 8, VCAM-1, and endothelin-1 are elevated in patients with SCD even in steady state.[113] Continuous inflammation and generation of oxygen radicals cause excessive utilization of antioxidants with a significant reduction in the total antioxidant reserves even in steady-state patients with SCD. Consequently, patients with SCD in steady state had significantly reduced total antioxidant status.[114] The risk of developing VOC correlates negatively with the levels of total antioxidant status,[114] suggesting that inflammatory oxidative stress contributes to red cell sickling and the pathophysiology of VOC.[115] Hence, SCD can be considered as a systemic chronic inflammatory disorder even during steady state in the absence of infection. However, the acquisition of infection by patients with SCD would certainly aggravate the background inflammatory response, generate more oxygen radicals, cause greater depletion of antioxidant reserves, and precipitate VOC.[116],[114] Moreover, continuing infection and inflammation would trigger humoral and cellular immune response as well as pro-coagulant acute phase response,[116] which will cause hyperviscosity [50] and hypercoagulability [117] with a strong predisposition toward VOC.

Cellular acute phase reaction: Neutrophilic leukocytosis and thrombocytosis

Modest neutrophilia due to redistribution of marginated neutrophils is a common feature of SCD even in steady state in the absence of infection.[118] Nonetheless, the prevalence and intensity of neutrophilia are higher in patients with SCD with bacterial infections.[103] Neutrophilic leukocytosis in patients with SCD with infection would have far-reaching consequences with respect to the pathophysiology of sickling. Infection-induced activation of neutrophils would trigger respiratory bursts leading to generation of more oxygen-free radicals and greater depletion of antioxidant reserves with higher risk of red cell sickling and VOC.[115],[114] Second, increased number of circulating activated neutrophils would lead to greater oxygen consumption, severer tissue hypoxia, and higher risk of VOC.[119],[120] Third, neutrophilia would aggravate blood viscosity,[121] which will adversely affect hemorheological and hemodynamic profiles and predispose to red cell sickling and VOC.[50] And fourth, neutrophils in SCD exhibit increased adherence to vascular endothelium and sickled red cells, which would predispose to VOC.[37] Thrombocytosis attributable to the background hemolytic anemia and autosplenectomy is also a common finding in patients with SCD even in steady state in the absence of any infection.[122] However, the intensity of thrombocytosis is higher in patients with SCD having superimposed bacterial infection.[123],[103] Similar to neutrophilia, thrombocytosis can cause adverse hemorheological alterations [121] that can precipitate VOC.[50] Moreover, sickling-induced vascular endothelial damage leads to subsequent exposure of subendothelial microfibrils and collagen. Exposure of these subendothelial fibers would cause contact activation of platelet and coagulation factors, which will lead to platelet aggregation, deposition of fibrin, and greater vaso-occlusion.[117],[124] It is noteworthy that the beneficial effect of hydroxyurea in the management of SCD is partly related to its ability to cause modest myelo-suppressive reduction in the number of neutrophils and platelets,[125] as well as attenuation of their activation and adhesiveness,[126],[127] thus counterbalancing their adverse roles in the pathogenesis of VOC.

Pyrexia, vomiting and diarrhea: Dehydration, hyperosmolality, increased HbS polymerization

Infection-associated pyrexia can arise as a result of endogenous pyrogenic effects of some inflammatory acute phase reactants such as TNF-α, or as a result of the effect of exogenous pyrogens associated with the invading pathogens, or as a result of a dual concert between endogenous and exogenous pyrogens.[128] In addition to fever, enteropathogenic organisms can also cause gastrointestinal dysmotility with severe diarrhea and/or vomiting.[129] Pyrexia increases the rates of perspiration and cutaneous water loss on the one hand, while diarrhea and vomiting invariably result in gastrointestinal loss of electrolytes and water on the other hand. Patients with SCD are particularly susceptible to dehydration due to their inability to conserve water as a result of recurrent renal papillary necrosis and hyposthenuria.[74] The net fluid and water loss due to combined effects of pyrexia, diarrhea, vomiting, and hyposthenuria can rapidly lead to dehydration, hyperviscosity, and VOC.[50] In addition to its role in causing dehydration, pyrexia is particularly dangerous in patients with SCD because higher temperatures significantly increase the rates of HbS gelation and polymerization with greater risk of red cell sickling and VOC.[73] Moreover, prolonged and uncorrected plasma dehydration can progress to red cell dehydration, which will elevate the MCHC, enhance polymerization of HbS, promote red cell sickling, and trigger VOC.[73] It is therefore of paramount importance that patients with SCD with infections, pyrexia, and/or dehydration should receive optimal fluid supplementation in addition to appropriate antibiotics.

Parasitic diseases: Protozoan and helminths: Erythrocytopathy, migratory pneumonitis, eosinophilia

The tropical environment within which the majority of patients with SCD live have very high prevalence of parasitic diseases. Yet, apart from Malaria, little is known about the roles of parasitic diseases in the pathophysiology of VOC in SCD. Many studies have been conducted on malaria in SCD. The malaria parasite is both erythrocytotropic and erythrocytopathic. Hence, malaria parasites invade and replicate within the red cells during the erythrocytic phase of the infection. The infected red cells consequently sickle as a result of metabolic changes induced by the replicating parasites.[130] The sickled red cells induce the formation of ICAM-1 and VCAM-1 adhesion molecules on the vascular endothelium to which they subsequently adhere.[131] The potency of malaria infection in inducing VOC may also be related to its special ability to induce the expression of histidine-rich protein knobs on the membrane surfaces of infected red cells.[132] These knobs confer upon malaria-infected sickled red cells the affinity for vascular endothelium leading to intercellular adhesion between sickled cells and endothelial cells.[132] Thus, malaria-infected sickled red cells have dual affinity for the endothelium due to the combined effects of cytoadhesion molecules (VCAM-1 and ICAM-1) on the endothelial cells and the cytoadherent effect of histidine-rich protein domains in the knobs of infected red cells.[131],[132] This dual predilection makes the malaria-infected sickle cells extremely adherent to the vascular endothelium, a situation that will promote stasis, red cell sickling, and VOC. It can thus be surmised that the ability of malaria parasite to directly induce sickling (by red cell invasion) and potentiate their adherence to endothelium (by inducing ICAM-1, VCAM-1, and histidine-rich protein knobs) are probably the principal factors that make malaria infection the most common and potent trigger of VOC in patients with SCD living in malaria endemic countries.[89] Until a potent malaria vaccine is eventually developed,[133] it is important to rely on continuous lifelong antimalarial chemo-prophylaxis in the management of these patients living in malaria endemic countries.[90] Very little or virtually nothing is currently known about the possible clinical significance of infections due to other erythrocytotropic agents such as the parasitic Babesia species [134] and the bacterial Bartonella species [135] in the pathogenesis of VOC in SCD. More research is needed to determine if these erythrocytotropic microbes are as efficient as malaria in inducing red cell sickling and adhesion in the pathophysiology of vascular occlusion and VOC.

There is relative paucity of literature with regards to the pathophysiologic roles of intestinal parasites as comorbid factors in patients with SCD in steady state and in the triggering of VOC. A study from the Middle East had reported that patients with SCD in steady state had relatively higher prevalence of protozoan and helminthic intestinal parasites as a result of their poor immune response to infection.[136] A study from Nigeria had revealed that steady-state hematocrit levels were significantly low among SCD patients infected with intestinal parasites as compared with those without intestinal parasites.[137] An uncontrolled case study from Nigeria had reported high prevalence of intestinal helminthic infections among SCD patients in VOC, suggesting a causal relationship between helminths infections and VOC.[138] However, the study did not expatiate on the pathophysiologic pathways through which intestinal parasites could have precipitated the VOC. We believe that intestinal parasites may possibly predispose to VOC by inducing eosinophilia because some studies have reported that activated eosinophils have been shown to adhere to vascular endothelium and contribute to the pathogenesis of VOC.[139] In addition, intestinal parasites may cause iron deficiency, which can raise blood viscosity and increase red cell aggregability,[140] and rheologically predispose to frequent VOC.[50] Moreover, some tropical parasitic diseases have the tendency to cause infiltrative pneumonitis syndromes, which may be associated with severe hypoxia and intense eosinophilia during the early migratory phases of the infections. These pulmonary syndromes include Loffler's syndrome in Ascariasis and Ancylostomiasis,[141] Katayama syndrome in Schistosomiasis,[142] Tropical Pulmonary Eosinophilia Syndrome in filariasis,[143] and Visceral Larva Migrans in Toxocariasis,[144] all of which may potentially progress to ACS and cause severe hypoxia. In all of these eosinophilic pneumonitis syndromes, the concert between pneumonitis-induced hypoxia and abundance of eosinophils with capacity to adhere to vascular endothelium [139] would predispose to red cell sickling and VOC. An isolated Nigerian study on Schistosomiasis in SCD had shown that apart from hematuria, established urinary Schistosomiasis in patients with SCD was also associated with pro-VOC rheological correlates such as iron deficiency,[140] eosinophilia,[139] secondary bacterial urinary tract infection, and neutrophilia,[37] all of which increase the frequency of VOC in SCD patients with urinary Schistosomiasis.[145]

There is the need to precisely define the pathophysiologic and prognostic significance of comorbid intestinal and urinary parasites in patients with SCD. Meanwhile, health care workers in the tropics must continue to counsel patients with SCD and their parents with respect to personal hygiene and environment sanitation as well as offer regular microbiological screening and early treatment of parasitic infections based on the existing World Health Organization recommendations for persons living in endemic areas.[146]

Obstructive respiratory dysfunction

The quality of respiratory noises is of clinical significance in discerning the site of respiratory obstruction. While snoring is usually suggestive of upper respiratory tract obstruction, wheezing is associated with lower respiratory obstruction. Both snoring and wheezing are undesirable in SCD because they cause hypoxemia and trigger VOC.

Upper airways obstruction: Adenotonsillar hypertrophy

Adenotonsillar hypertrophy (ATH) is a common problem in SCD and is thought to occur as a result of compensatory response to autosplenectomy and/or recurrent tonsillitis due to sickle cell immune dysfunction.[147] The prevalence of obstructive ATH among children and adolescents with SCD may be as high as 55.3% and is often associated with other problems, including difficulty in eating, recurrent tonsillitis, snoring and sleep apnea,[147] as well as nocturnal oxygen desaturation and hypoxemia.[148] Hence, ATH is a potent trigger of red cell sickling and is a recognized risk factor for recurrent VOC.[147],[148] It is, therefore, important to recognize obstructive ATH and arrange for early surgical intervention (after careful preoperative assessment and optimization) for a lasting relief from recurrent VOC.

Lower airways obstruction

Wheezing in patients with SCD is of triple differential diagnostic significance. Wheezing may be due to comorbid primary asthmatic disease, or it may simply be the pulmonary manifestation of SCD (the so-called nonasthmatic wheezing), or it may be due to NSAIDs (the so-called NSAID-induced asthma). It is the responsibility of the health care giver to distinguish between these three differential diagnoses for effective management and future prevention.

Asthma and asthma-like syndrome (nonasthmatic wheezing)

Airway obstruction and wheezing have been reported to be a common problem among patients with SCD. The prevalence of asthma among patients with SCD as variously reported by cohort studies ranged from 17% to as high as 41%.[149] Nonetheless, some studies have demonstrated that up to 30% of patients with SCD had recurrent episodes of wheezing with dyspnea, out of which almost half did not have a diagnosis of asthma.[150] Hence, not all wheezing in patients with SCD is due to asthma.[149],[150] These findings support the concept that an asthma-like syndrome (nonasthmatic wheezing) may actually be a pulmonary manifestation of SCD. The underlying pathophysiologic basis of airway obstruction in asthma-like syndrome in SCD includes airway hyperresponsiveness, increased T-helper-2 activity and hypercytokinemia with an exaggerated inflammatory response.[151] Other studies have suggested that nonasthmatic wheezing in SCD may be due to lower airway obstruction related to increased cardiac output and increased pulmonary blood volume in response to chronic anemia.[152] The lung is an important organ in SCD because it is responsible for oxygenation and re-oxygenation of deoxy-HbS and conversion of reversible sickle cells to discocytes. It is, therefore, not surprising that both asthma and nonasthmatic wheezing are strongly associated with frequent occurrence of VOC and ACS in patients with SCD.[153] Hence, any form of airway obstruction irrespective of whether it is asthmatic or nonasthmatic in origin can aggravate hypoxia and trigger VOC in SCD patients and must be properly evaluated and managed according to blood gas parameters.

NSAID-induced asthma: Caution during SCD analgesia

NSAIDs are commonly used to treat pain due to SCD. However, it should be appreciated that aspirin and other NSAIDs may cause or exacerbate asthma in susceptible persons. NSAIDs induce asthma by inhibiting cyclo-oxygenase-1 (COX1), leading to reduced production of the bronchodilator prostaglandin E2.[154] Reduced COX-1 activity is also accompanied by overproduction of cysteinyl leukotrienes that are associated with bronchospasm.[154] The combined effects of low prostaglandin E2 and high levels of cysteinyl leukotrienes are thought to be responsible for NSAIDs-induced asthma.[154] Recent data have suggested that even paracetamol (acetaminophen), which is a centrally acting COX-3 (a COX-1 variant) inhibitor with an analgesic and antipyretic properties but little or no antiinflammatory effect, may rarely cause or exacerbate asthma in genetically susceptible subjects.[155] Other reports suggest that selective COX-2 NSAIDs did not induce bronchospasm in patients. NSAID-induced asthma [156] may therefore be safer in the management of VOC in patients with SCD with family or personal history of asthma. Nonetheless, extreme caution must be exercised even with the use of selective COX-2 inhibitors because an isolated study had questioned their safety in patients with NSAID-induced asthma.[157] Another concern is the possibility that excessive use of selective COX-2 inhibitors may synergistically exacerbate the thromboembolic and cardiovascular risks associated with SCD.[158],[159] Hence, there is need for caution when using NSAID or even paracetamol in the treatment of VOC in patients with SCD having a positive personal or family history of asthma.

Malignant diseases

Comorbid malignant diseases will certainly aggravate anemia in patients with SCD disease through multiple mechanisms ranging from direct marrow infiltration to hemorrhage, excessive utilization of folate by tumor cells, and the marrow suppressive effect of cancer-induced inflammation.[160] Moreover, cancer-induced inflammations [161] would be expected to aggravate oxidative stress, deplete antioxidant reserves, increase the rate of red cell sickling, and ultimately elevate the risk of VOC.[115] In addition to marrow infiltration, certain malignant diseases such as leukemias and myelomas are particularly associated with adverse rheological changes that will also predispose to more frequent VOC.

Hematological cancers: Blood rheology and viscosity

Leukocytosis: Leukemias

From pathophysiologic point of view, the effects of leukemic leukocytosis on the risk of VOC in patients with SCD will depend on the leukocyte cell type. On the one hand, lymphoid leukemias would principally raise the risk of VOC by mass effect resulting in hyperviscosity,[121] which is an established risk factor for VOC.[50] On the other hand, myeloid leukemias with neutrophilia, would raise the risk of VOC due to a combination of hyperviscosity [50],[121] and the inherent adhesiveness of neutrophils to vascular endothelium.[37]

In one case report, a SCD patient presented as a case of VOC, but acute lymphoblastic leukemia (ALL) was subsequently diagnosed after a blood count revealed excess blasts.[162] This case suggested that acute leukemia could actually raise blood viscosity and trigger pain crisis and present as VOC in SCD patients.[162] Hence, all cases of VOC with significant number of immature cells in their blood should be carefully evaluated to rule out acute leukemia, notwithstanding the fact that infection (an important trigger of VOC) can also induce a left shifted blood picture with circulating immature blood cells. It was reported in another case of SCD patient treated for ALL that leukemic relapses were always associated with severe VOC, which sometimes occurred at the time of bone marrow relapse even before the appearance of blasts in the peripheral blood.[163] This report suggests that acute leukemia relapse may precipitate VOC by causing intramedullary infiltration, stasis, and hypoxia, which would subsequently be accentuated by hyperviscosity when the blasts proliferate and eventually appear in large numbers in the peripheral blood.[163] Therefore, the occurrence of VOC in SCD patient with acute leukemia in remission may be an indicator or a harbinger for relapse. SCD patients with acute leukemias should whenever possible be considered for stem cell transplant as a treatment option that can potentially eradicate both diseases.

High leukocyte count in chronic myeloid leukemia (CML) has been associated with increased incidence of leukostasis-induced acute vaso-occlusive complications even in individuals with SCT.[164] The pathophysiologic role of high leukocyte count in the frequent occurrence of VOC is even more clearly demonstrated in patients with SCD with CML.[165],[166] Predictably, reduction of leukocyte count following successful treatment with conventional chemotherapeutic drugs (nontyrosine kinase inhibitors) was associated with reduction in the frequency of VOC.[165],[166] It must be appreciated that in these cases, the beneficial effect on VOC was not due to the drugs themselves but rather it was the result of the decrease in leukocyte count and reduced blood viscosity.[165],[166] However, in the first reported case where a patient with SCD and comorbid CML received imatinib (a tyrosine kinase inhibitor), the treatment was also predictably associated with reduction in leukocyte count and a commensurate fall in the frequency of VOC.[167] Moreover, discontinuation of imatinib in this particular case led to the recurrence of VOC, which was not explained by resurgence of leukocyte count or by changes in HbF levels.[167] This incidental finding strongly suggests that imatinib is capable of preventing VOC in SCD through an unidentified mechanism that is independent of leukocyte count reduction. Thus, the role of tyrosine kinase inhibitors as potential drugs in the prevention of VOC in SCD should be vigorously investigated.

Hyperproteinemia: Myelomas

Myeloma is associated with increased production of immunoglobulins, which cause plasma hyperviscosity with a resultant increase in red cell aggregability. Plasma hyperviscosity and red cell aggregability are undesirable in patients with SCD in whom they are associated with increased red cell sickling, which increases the frequency and severity of VOC as reported in SCD patients with myeloma.[168],[169],[22] The frequencies of VOC in such cases can be reduced by intensive plasmapheresis or exchange blood transfusions in the short term.[169] However, in the long term the frequent VOC can only be effectively controlled if definitive chemotherapy is directed against the myeloma disease itself. Interestingly, a recent study has demonstrated that Pomalidomide (a derivative of Thalidomide) is capable of treating both myeloma and SCD.[170] This is because Pomalidomide can kill malignant plasma cells and simultaneously increase the production of fetal hemoglobin, which is known to inhibit HbS polymerization, reduce red cell sickling, and diminish the frequency of VOC.[170] Therefore, resurgence of VOC may be a harbinger of relapse in patients with SCD with myeloma in remission. Eligible patients with SCD and comorbid myeloma should always be considered for stem cell transplant that is capable of simultaneously eradicating both myeloma and SCD.

Solid cancers: Intratumor sickling and crisis

A limited number of case reports of solid tumors in patients with SCT or SCD suggest that adverse vascular events, including intratumor red cell sickling and crisis, may occur as a result of abnormal intratumor microenvironment.[171] Tumor hypoxia coupled with stasis due to long transit times in the abnormally tortuous tumor microcirculation were thought to be responsible for triggering red cell sickling and intratumor crisis as reported in SCT patients with cervical cancer [172] and gliomas.[173] Moreover, in vivo evidence suggests that sickle red blood cells preferentially accumulate in the microvasculature of rat gliomas relative to normal brain tissue as demonstrated by magnetic resonance imaging (MRI) techniques using radiation-labeled sickle red blood cells.[174] The combined effects of abnormal microvasculature, hypoxia, and lactic acid production within the tumor were thought to be responsible for inducing red cell sickling and subsequent sequestration of sickle red cells by the tumor.[172],[173],[174] These findings suggest that SCT and SCD patients with solid tumors may experience recurrent intratumor sickling crisis that may manifest as increased tumor pains resulting from the pathophysiologic cascade of tumor hypoxia, lactic acidosis, red cell sickling, sickled red cell sequestration, ischemia, and infarction.[173] Hence, intratumor crisis and pain in SCD patients with widespread solid tumor metastasis may be indistinguishable from the classical generalized VOC. Apart from inducing pain, intratumor sickling is undesirable because it aggravates solid tumor hypoxia, which is considered as an adverse prognostic factor for disease progression and resistance to systemic chemotherapy and radiotherapy.[175] Nonetheless, because of the tendency of solid tumors to induce sickling and sequester sickled red cells, some researchers are focusing on the possibility of using cytotoxic drug-loaded HbS containing red cells to specifically target hypoxic tumor microvasculature with the aim of delivery localized and effective chemotherapy with minimal systemic adverse effects.[176]

Drug abuse and addiction

The vast majority of patients with SCD are teenagers and young adults who may succumb to peer group pressure to drink, smoke, or even take street drugs. Alcohol, tobacco, and street drugs are harmful to everyone, but they are especially dangerous to those with SCD in whom they can trigger VOC through a number of pathophysiologic mechanisms.

Cigarette smoking: Respiratory irritation, carbon monoxide inhalation, hypoxia

Smoking is irritating to the respiratory tract and predisposes to recurrent infection and inflammatory pneumonitis that may progress to chronic obstructive pulmonary disease,[177] which would reduce red cell oxygenation and cause sickling. Cigarette smoke is also rich in carbon monoxide. The affinity of carbon monoxide for hemoglobin is exceedingly higher than that of oxygen.[178] During smoking, occupation by carbon monoxide of oxygen binding sites on heme reduces the oxygen content of circulating blood.[178] Moreover, carbon monoxide also paradoxically increases the oxygen affinity of the remaining heme sites and shifts the hemoglobin–oxygen dissociation curve to the left.[179] Hence, carbon monoxide reduces the blood's oxygen carrying capacity (hypoxemic effect) and simultaneously reduces the rate of release of oxygen to the tissues (hypoxic effect). This dual effect of hypoxemia and hypoxia would trigger the renal oxygen sensor responsible for erythropoietin release with a resultant increase in erythropoietin and the hematocrit.[94],[180] In addition, carbon monoxide is thought to reduce plasma volume,[181] which would aggravate the erythropoietin-induced increment in hematocrit. Therefore, smoking would be highly deleterious in patients with SCD because both rising hematocrit and falling plasma volume are important determinants of hyperviscosity, which is a well-established trigger of VOC.[50] It should also be appreciated that smoking can also cause neutrophilia,[182] lymphocytosis,[183],[184] thrombocytosis,[185],[180] and hyperfibrinogenemia,[185] all of which can predispose to VOC by aggravating blood viscosity [50] and/or increasing neutrophil–endothelial interaction.[37] Hence, the overall hemorheological consequences of smoking [186] are in tandem with the hemorheological prerequisites for VOC.[50] Furthermore, research in otherwise healthy individuals has demonstrated clinically significant correlations between tobacco smoke exposure and the development of inflammation, oxidative stress, and endothelial dysfunction, all of which are capable of triggering red cell sickling and VOC in patients with SCD.[187] Clinical evidence suggests that active smoking is as harmful as passive smoking with respect to VOC in SCD patients.[187] This is corroborated by previous studies, which have demonstrated increased frequencies of VOC and hospitalization among children [188] and adults [189] with SCD in relationship to both active smoking and passive exposure to cigarette smoke.

The deleterious effects of moderate to high exposure to carbon monoxide among active and passive smokers with SCD are well established, as highlighted in earlier paragraph. Nonetheless, regulated exposure to lower levels of carbon monoxide may paradoxically be of therapeutic value in SCD. Earlier it was suggested that carbon monoxide could prolong the lifespan of red cells in patients with SCD.[190] A more recent study in transgenic mice had also suggested that exposure to low levels of carbon monoxide and PEGylated carboxyhemoglobin had cyto-protective, vasodilator, and antiinflammatory properties, all of which would potentially enhance perfusion, protect against cell injury, reduce tissue ischemia, and mitigate VOC in patients with SCD.[191] Interestingly, some studies have revealed that higher levels of atmospheric carbon monoxide were associated with lower numbers of hospital admissions due to acute pain in patients with SCD living in urban areas.[192] These apparently, opposed the divergent roles of carbon monoxide as a “stressor” and/or “reliever” in sickle cell vaso-occlusive processes call for further studies to determine the precise role of carbon monoxide and its dosage effect on SCD pathophysiology.

Alcohol abuse: Alcohol-induced sickling, diuresis, dehydration

Alcohol abuse is common in patients with many types of chronic painful medical disorders. This may be attributed to the pain-dampening effects of alcohol, which is often used as self-medication by persons with painful conditions.[193] However, alcohol abuse is particularly dangerous for patients with SCD because alcohol-induced CNS depression [194] can undesirably potentiate the CNS depressant effects of prescription narcotic analgesics that are commonly employed in the treatment of VOC.[195] Moreover, alcohol-induced diuresis [196] would aggravate sickle cell hyposthenuria [74] and raise plasma osmolality and viscosity, cause red cell dehydration, and increase MCHC, all of which would trigger VOC.[50],[73] The adverse pro-sickling effects of the aforementioned blood changes would counterbalance any potentially beneficial antisickling effect (i.e. raised MCV with reduced MCHC) that may ensue as a result of alcohol-induced macrocytosis.[197] Hence, previous studies had demonstrated that alcohol consumption induces red cell sickling [198] and causes VOC [199] in patients with SCD. Nonetheless, an isolated study had shown that alcohol abuse among patients with SCD was paradoxically associated with fewer emergency room visits due to pains.[200] These findings were thought to be related to alcohol enhancement of the patients' coping mechanisms through attention diversion and reduction in pain perception, which lead to ignoring painful episodes.[200] It is also possible that the pain-dampening effect of alcohol may confer greater coping mechanism in SCD patients who abuse alcohol.[193] It may, therefore, be deduced that alcohol abuse is particularly dangerous in SCD because on the one hand alcohol induces red cell sickling and VOC,[198],[199] while on the other hand it reduces pain perception and sensation [193],[200] that might ultimately lead to symptom neglect and failure to seek timely and essential medical care. Therefore, alcohol use must be strongly discouraged in patients with SCD.

Clinical procedures and interventions

SCD is a chronic and lifelong disorder. The myriad of acute and chronic complications of SCD compel the patients to frequently visit hospitals on routine and emergency basis. Each visit attracts appropriate investigations and clinical interventions, some of which are not entirely innocuous and may directly or indirectly precipitate VOC.

Blood transfusion reactions

SCD is a chronic hemolytic state, which often leads to multiple blood transfusions. Multiple blood transfusions increase the risk of allo-immunization and immune reactions against a wide range of nonerythroid [201],[202] and erythroid [203] antigens of the donor blood. The risk of allo-immunization in multiply transfused patients is even higher if the patients and donors belong to different racial extractions, as is usually the case with SCD patients living in Europe and North America where the donors are predominantly Caucasians.[203] Different types of transfusion reactions can trigger VOC through different pathophysiologic pathways. Nonhemolytic febrile transfusion reactions in patients with SCD are potential triggers of VOC because fever increases the rate of HbS polymerization, which predisposes red cell sickling and VOC.[73] Allergic and urticarial transfusion reactions may be associated with bronchospasm, respiratory distress, and hypoxia that may potentially trigger VOC in patients with SCD.[204] Similarly, transfusion-related acute lung injury, which is due to leuko-agglutinins in donor plasma may also cause severe wheezing and respiratory distress with hypoxia that may precipitate VOC in SCD patients.[205] Acute hemolytic transfusion reactions are quite rare within the setting of diligent pretransfusion cross-match procedures. However, delayed hemolytic transfusion reactions (DHTR) due to anamnestic immune response to previously encountered red cell antigens still pose a significant transfusion challenge in patients with SCD.[206] DHTR is particularly detrimental in SCD for at least four reasons. First, DHTR may cause significant intravascular hemolysis of donor and patient red cells,[206] which will lead to hemoglobinemia, nitric oxide quenching, endothelial dysfunction, and impairment of vasodilatation.[207] Second, intravascular hemolysis may cause the release of phosphatidylserine, which would become adsorbed onto patient's sickle red cells and mediate their adherence onto the vascular endothelium.[208] Third, DHTR is associated with fever, which increases the rate of HbS polymerization.[73] Fourth, continuing intravascular hemolysis in DHTR would cause depletion of the plasma haptoglobin and hemopexin with a resultant accumulation of free heme in the plasma wherein it promotes oxidative inflammatory changes, red cell sickling, and VOC.[209] All of the aforementioned four pathophysiologic attributes of DHTR can concertedly predispose to VOC in patients with SCD. It is, therefore, not surprising that DHTR regularly triggers VOC in patients with SCD.[206],[210] Hence, DHTR should be considered as an important differential diagnosis in SCD patients who present with VOC within a few days after blood transfusion. However, the management of DHTR in SCD calls for caution because systemic use of steroids may potentially trigger more VOC in patients with SCD.[84] Therefore, other forms of immunosuppressive agents such as intravenous immunoglobulin, rituximab, or anti-C5-compliment antibodies may be safer than corticosteroids in halting the hemolytic process of DHTR in patients with SCD.[211],[212]

Erythropoietin therapy

The kidneys of patients with SCD are vulnerable to red cell sickling and ischemia mainly due to high oxygen extraction in the renal medulla, which is characterized by low oxygen tension, low pH, and high osmolality.[213] Recurrent sickling within the kidneys leads to the development of sickle cell nephropathy (SCN), the pathology of which is dominated by ischemic changes and vasculopathy with a combination of both glomerular and tubular damage that clinically manifest as impaired urinary concentration, hematuria, proteinuria, and chronic renal insufficiency.[213] Patients with SCN have diminished creatinine clearance, reduced erythropoietin production, low hemoglobin levels, and transfusion dependence.[213],[214] However, erythropoiesis of patients with SCD and nephropathy can be stimulated by erythropoietin, which can be given with or without hydroxyurea and/or iron supplementation.[214] Erythropoietin therapy is undoubtedly beneficial in minimizing transfusion dependence associated with SCD nephropathy. Nonetheless, there are theoretical concerns about possible crisis-inducing adverse effects of hematological response to erythropoietin therapy in SCD. This is more likely to occur if erythropoietin is given in the absence of concurrent hydroxyurea therapy.[214] Optimal hematological response to erythropoietin would include increasing reticulocytosis and rising hematocrit, both of which may jointly predispose to VOC.[214] This is because sickle reticulocyte membrane has abundant expression of the α4β1-integrin complex that binds endothelial VCAM-1 receptors as an important primary event in the initiation of VOC,[215] while rising hematocrit levels may cause hyperviscosity, which is another important risk factor for VOC.[50] For these reasons, erythropoietin therapy in SCD is a potential trigger for VOC. Hence, the dosage of erythropoietin for SCD patients should be closely monitored and carefully adjusted in order to avoid abrupt raise in reticulocyte count and hematocrit to levels that can trigger VOC.

Renal transplant

Erythropoietin therapy is undoubtedly beneficial for patients with SCD who are hemodynamically stable with mild to moderate renal insufficiency.[214] However, renal transplant therapy is required in these patients with uremia, circulatory overload, pulmonary edema, and end-stage renal disease.[216] Adequate histocompatibility and preoperative optimization can lead to a successful renal transplant.[216] Nonetheless, previous studies had revealed an increase in frequency of VOC in patients with SCD who underwent successful renal transplant.[216],[217] This phenomenon was attributed to rebound posttransplant reticulocytosis, polycythemia, and hyperviscosity resulting from restoration of erythropoietin production by the transplanted kidney.[218] Recurrent VOC in the posttransplant period is highly undesirable because it may lead to intragraft sickling with vascular occlusion that had been shown to adversely affect blood flow and survival of renal grafts in patients with SCD.[219] Hence, SCD who receive renal transplant must be carefully monitored to ensure that recurrent VOC is prevented by assessing serial hematocrit levels and performing venesection if posttransplant polycythemia is detected.[218] While reducing HbS concentration by exchange transfusion would reduce the risk of VOC, the incorporation of hydroxyurea in the posttransplant immunosuppression regime had been suggested as a practical way of stimulating the production of HbF, which will protect the patient with SCD and the transplanted kidney from the adverse effects of recurrent VOC.[220]

Radiological contrast media

With improvement in medical care, patients with SCD would continue to live longer with increased incidence of multiple organ damage and dysfunctions that may require detailed radiological evaluations. Conventional intravenous iodinated radiographic and CT enhancement contrast media have traditionally been contraindicated in patients with SCD because of their high osmolality and hypertonicity.[221] The hypertonicity associated with these contrast media induces osmotic shrinkage of red cells, which increases intracellular HbS concentration, HbS polymerization, and red cell sickling that subsequently precipitate VOC.[221] The newer second-generation low- and iso-osmolar iodinated contrast agents are associated with reduced red cell shrinkage and lower risk of triggering VOC.[221] The risk of triggering VOC and occurrence of other adverse effects can be reduced even further by ensuring that patients with SCD are adequately optimized before administering iodinated contrast media. This can be achieved by infusion of fluids for optimal hydration, administration of oxygen and/or blood transfusion before injecting the contrast media.[222]

Gadolinium-based contrast media (GBCM) are usually used for MRI. The GBCM are generally well tolerated in general radiology practice as incidence of adverse reactions are encountered at much lower rate than is observed with the use of iodinated contrast media.[223] Osmolality is of little significant as far as safety is concerned with the use of GBCM because of the low injection dose utilized at MRI.[223] Hence, GBCM is probably safer than iodinated contrast media in patients with SCD. A small retrospective case–control study found no significantly increased risk of VOC or hemolytic adverse events when GBCM were administered for MRI studies in patients with SCD.[224] The safety of GBCM in SCD was confirmed by other small scientific studies in which patients with SCD were evaluated by MRI with GBCM without adverse effects.[225],[226],[227] These studies suggest that the risk to sickle cell patients from intravenous administered GBCM at currently approved dosages for MRI must be extremely low; however, larger studies are needed to validate the findings of these small studies. Nonetheless, we believe that the best way of preventing contrast media-induced VOC is to reduce the concentration of HbS and the number of HbS containing red cells by exchange blood transfusion before administering any contrast media (whether iodinated or gadolinium based).

Cancer chemotherapy

The incidence of malignant diseases among patients with SCD would probably continue to rise as a result of better clinical care with increasing survival [228] coupled with the long-term use of the potentially mutagenic drug hydroxyurea.[229] Moreover, long-term survivors of SCD in Africa would be particularly at increased risk of acquiring locally prevalent and transfusion transmissible viruses such as hepatitis B and C and HIV that frequently predispose to cancers.[230],[231] While cancers in patients with SCD should be treated adequately, it should be appreciated that systemic chemotherapy for tumors may trigger VOC in patients with SCD. Notable among these are specific chemotherapeutic drugs such as paclitaxel [232] and capecitabine [233] that are associated with VOC in patients with SCD. In some cases VOC was blamed on a combination rather than specific chemotherapeutic drugs. For example, VOC was reported to have been triggered by Cyclophosphamide, Oncovin, Procarbazine and Predinisolone (COPP) combination chemotherapy for Hodgkin lymphoma.[234] Proposed mechanisms for triggering red cell sickling by chemotherapeutic agents include the induction of membrane phospholipid damage via the apoptotic cascade of erythrocytes (eryptosis) during the administration of these drugs especially paclitaxel.[232],[235] However, other cytotoxic drugs such as docetaxel [236] and cisplatin [237] are also known to induce eryptosis but have not yet been specifically associated with triggering sickle cell VOC. It should be appreciated that prednisolone, which is a commonly embedded steroid within many combination chemotherapy regimens, is also capable of triggering VOC.[84] Therefore, SCD patients on cancer chemotherapy must be carefully monitored for the occurrence of VOC.

Granulocyte growth factor therapy

Neutrophils have been shown to be primary participants in VOC because of their tenacious interactions with vascular endothelium.[37] It is, therefore, not surprising that the use of growth factors such as G-CSF was associated with VOC in patients with SCD as well as in apparently healthy persons with SCT.[238] The G-CSF had been associated with triggering VOC within the whole spectrum of the sickling disorders ranging from the apparently healthy SCT [239] to severe SCD such as SCA (HbSS)[240] as well as mild SCDs such as HbSC [241] and HbS-beta-thalassemia.[242] The use of G-CSF in SCD had triggered VOC even when the growth factor was locally applied intralesionally for the treatment of leg ulcers.[240] Similarly, when G-CSF was administered for the purposes of autologous stem cell mobilization procedures in SCD patients with malignancies, it triggered variable degrees of vaso-occlusive morbidities ranging from isolated VOC episodes to VOC complicated by disseminated intravascular coagulation with multiorgan damage [242] and even death in some cases.[243] There are at least two possible basic pathophysiologic mechanisms that trigger VOC when G-CSF is used in individuals with SCT and SCD. First, the G-CSF causes neutrophilic leukocytosis that can increase the number of adherent neutrophils on the endothelium [37] and raise whole blood viscosity,[121] which is an important risk factor for VOC.[50] Second, G-CSF activates neutrophils with a resultant increase in their adhesiveness to vascular endothelium, thereby further increasing the risk of VOC.[244] These mechanisms underscore the need for extreme caution when considering the use of G-SCF in individuals with SCT and SCD. However, if it is absolutely necessary to use G-CSF in such individuals, especially in SCD, the risk of VOC should be minimized by reducing the HbS level via an intensive exchange transfusion schedule before administering the growth factor.[238]

Steroid therapy

There are controversies regarding the effects of steroids in patients with SCD. Dexamethasone has been shown to have short-term beneficial effects in SCD patients with VOC [245] and ACS [246] by reducing the duration of hospitalization and length of analgesic therapy. However, these initial benefits are counterbalanced by the high frequency of rebound VOC, which has greatly diminished the initial enthusiasm for the use of dexamethasone in these patients. As patients with SCD access better clinical care and live longer, they are sometimes prescribed long-term steroids for the treatment of various chronic autoimmune and inflammatory conditions ranging from autoimmune hemolytic anemia to systemic lupus erythematosus, polyarteritis nodosa, rheumatoid arthritis, Crohn's disease, and sarcoidosis.[247] Despite the antiinflammatory effect of steroids, previous studies have reported increased incidence and severity of VOC among patients with SCD on long-term treatment with intraarticular [248] or systemic corticosteroids.[84] The risk of VOC correlated with the intensity of steroid-induced neutrophilic leukocytosis.[247] Hence, it is thought that steroid-induced neutrophilic leukocytosis was responsible for the increase in the frequency of VOC observed in patients with SCD treated with corticosteroids.[247] However, treatment with hydroxyurea and exchange transfusion programs led to the regression of the frequency of pain episodes in patients with steroid-induced VOC.[247] Therefore, corticosteroids should be used with caution in patients with SCD, and it is recommended that in order to prevent or reduce the risk of recurrent VOC, a chronic exchange blood transfusion regimen or hydroxyurea therapy should be considered before starting long-term steroid treatment in patients with SCD.

Despite the widespread use of steroids for treatment of asthma and allergies, glucocorticoids may paradoxically cause allergic reactions, anaphylaxis, and bronchospasm.[249] Corticosteroid-induced bronchospasm should be considered when asthmatic patients fail to improve or deteriorate with systemic corticosteroid therapy.[249] Steroid-induced bronchospasm can affect any person, but it is more likely to occur in patients with history of aspirin-induced allergy and bronchospasm.[250] Hence, the dual adverse potentials of steroid as trigger of VOC [84],[248] and inducer of bronchospasm [249] call for special caution when contemplating the use of steroids for whatever indication in patients with SCD.

Phosphodiesterase inhibitor therapy

The phosphodiesterase (PDE)-5 inhibitors reduce the rate of cyclic guanosine monophosphate (cGMP) breakdown, thereby prolonging and amplifying nitric oxide-mediated signals, which could potentially inhibit and reverse the vasculopathic changes associated with SCD pulmonary hypertension (PH).[251] Consequently, sildenafil was approved by the Food and Drug Administration in the USA for the management of PH in the general population, and initial reports suggested that sildenafil could reduce pulmonary arterial pressure and improve exercise tolerance in patients with SCD-PH.[252] However, the findings of these preliminary studies were not confirmed by a more recent National Institutes of Health-sponsored multicenter clinical trial of sildenafil in SCD-PH.[253] Moreover, the trial was prematurely terminated due to a higher percentage of subjects experiencing serious adverse events with disproportionately high frequency of hospitalization for pains in the sildenafil arm.[253] Sildenafil is not known to induce red cell sickling, hence the precise pathophysiologic mechanism by which it triggers pain in SCD patients is not yet clear. However, it is known that sildenafil is commonly associated with backaches and myalgia as side effects even in non-SCD individuals.[253] It has thus been hypothesized that sildenafil might lower pain threshold by interfering with nitric oxide-cGMP signaling, thereby enhancing pain perception and increasing the number of pain episodes in SCD patients.[253] Nonetheless, one study had reported that sildenafil paradoxically relieves priapism in patients with SCD without inducing VOC,[254] and a randomized controlled trial of sildenafil for preventing recurrent ischemic priapism in SCD did not report any VOC and concluded that sildenafil use by systematic dosing may offer a strategy to prevent recurrent priapism in SCD.[255] However, the fact that sildenafil had been reported to cause priapism in persons with SCT [256] and trigger VOC in patients with SCD [253] calls for extreme caution when contemplating the use of PDE-5 inhibitors for whatever indications in patients with SCD.


  Conclusion Top


VOC in patients with SCD can be triggered by a myriad of etiological risk factors through multiple and sometimes overlapping pathophysiologic mechanisms. It is, therefore, necessary for the hematologist to thoroughly investigate all cases of VOC in patients with SCD in order to identify the actual etiological and pathophysiologic factors for the crisis. This approach will enable the hematologist to offer appropriate counseling for these patients to avoid undue exposure to risk factors in the future. In situ ations where patient exposure to risk factor is unavoidable, the patients should be optimized to withstand the risk factors through the use of clinical interventions such as conditioning of ambient temperature, appropriate clothing, optimal hydration, oxygen supplementation, vaccination and antimicrobial chemotherapy/prophylaxis, exchange blood transfusion, or hydroxyurea as the case maybe in order to obviate VOC with its attendant risk of organ damage. Moreover, counseling and/or the use of anxiolytics and antidepressants may be essential in reducing the frequency of VOC in patients with SCD with comorbid psychological disorders.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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