Sickle cell disorders: Clinical guidelines

List of Abbreviations

AVM – arteriovenous malformation

ALT – alanine aminotransferase

AST – aspartate aminotransferase

aPTT – activated partial thromboplastin time

IVIG – normal human immunoglobulin products for intravenous administration (Immunoglobulins, normal human, for intravascular administration, ATC code J06BA02)

HIV – human immunodeficiency virus

DIC – disseminated intravascular coagulation

DNA – deoxyribonucleic acid

GI – gastrointestinal tract

CT – computed tomography

PH – pulmonary hypertension

LDH – lactate dehydrogenase

INR – international normalized ratio

MRA – magnetic resonance angiography

MRI – magnetic resonance imaging

UIBC – unsaturated iron-binding capacity

NSAIDs – non-steroidal anti-inflammatory drugs

TS – transferrin saturation

ACS – acute chest syndrome

TIBC – total iron-binding capacity

ARF – acute renal failure

ASS – acute splenic sequestration

PT – prothrombin time

PCR – polymerase chain reaction

GVHD – graft-versus-host disease

SAH – subarachnoid hemorrhage

SCD – sickle cell disease

MODS – multiple organ dysfunction syndrome

FES – fat embolism syndrome

HSCT – hematopoietic stem cell transplantation

TIA – transient ischemic attacks

US – ultrasound examination

CRF – chronic renal failure

CNS – central nervous system

ALP – alkaline phosphatase

ECG – electrocardiography

EchoCG – echocardiography

AB0 – ABO blood group system

ASA – acetylsalicylic acid**

Ig – immunoglobulin

Hb – hemoglobin

HbF – fetal hemoglobin

HbSC – compound heterozygous carrier state for two abnormal hemoglobins, HbS and HbC

HbSS – sickle cell anemia (homozygosity for abnormal HbS)

HLA – human leukocyte antigen system

MCV – mean corpuscular volume

PaO₂ – partial pressure of oxygen

PLT – platelets

Rh – Rhesus factor

sO₂ – oxygen saturation

S-β-thalassemia – compound heterozygosity for abnormal HbS and β-thalassemia (sickle cell-beta thalassemia)

t-PA – tissue plasminogen activator

TV – television

WBC – white blood cells

** – vital and essential drugs

# – drug used off-label (not in accordance with the indications, contraindications, routes of administration, or dosages specified in the drug's package insert)

Terms and Definitions

Avascular necrosis – ischemic necrosis of a bone fragment, i.e., necrosis resulting from insufficient blood supply

Adenoidectomy – surgical removal of the adenoids

Alloimmunization – production of antibodies against antigens from other individuals

Anemia – decrease in hemoglobin concentration

Asplenia – absence of the spleen

Vaccine prophylaxis – specific prevention of infectious diseases through vaccination

Hepatomegaly – enlargement of the liver

Erythroid bone marrow hyperplasia – increase in the number of tissue structural elements through excessive new formation

Hyposthenuria – inability to concentrate urine

Dactylitis – a condition characterized by an inflammatory process in one or more fingers or toes

Deoxyhemoglobin – the form of hemoglobin in which it is capable of binding oxygen or other compounds

Stroke – acute cerebrovascular accident accompanied by sudden loss of consciousness and paralysis

Kyphotic deformity – curvature of the spine in the sagittal plane with a posteriorly facing convexity

Contraception – prevention of pregnancy using contraceptive means

Laparoscopy – a modern surgical method in which operations on internal organs are performed through small (usually 0.5–1.5 cm) incisions

Neutropenia – a decrease in the number of neutrophils in peripheral blood.

Nocturia – predominance of nocturnal diuresis over daytime diuresis

Normochromic anemia – anemia with a normal color index (normal MCH) of red blood cells.

Osteomyelitis – infectious inflammation of all components of bone tissue: the bone, periosteum, and bone marrow

Osteonecrosis – necrosis of bone tissue resulting from poor blood supply

Osteopenia is a bone tissue condition characterized by a decrease in bone mineral density, leading to bone fragility and an increased risk of fracture

Acute chest syndrome – acute chest pain associated with pulmonary infarction due to vessel occlusion in sickle cell disease

Pure red cell aplasia – a disease or syndrome characterized clinically and by laboratory findings of profound anemia and selective (pure) aplasia of the erythroid lineage alone

Penicillin prophylaxis – the use of beta-lactam antibacterial drugs (penicillins) to prevent infections caused by susceptible pathogens

Prenatal diagnosis – comprehensive antenatal diagnostic assessment aimed at detecting pathologies during intrauterine development

Priapism is an involuntary, persistent erection unrelated to sexual arousal

Proliferative angiopathy – impaired blood vessel permeability caused by vascular endothelial thickening

Protrusion is the initial stage of intervertebral disc herniation

Rhabdomyolysis – a syndrome characterized by the destruction of muscle tissue cells, a sharp increase in creatine kinase activity and myoglobin levels, myoglobinuria, and the development of acute renal failure

Sickle cell disease is a group of conditions caused by specific mutations in the beta-globin gene that alter the physicochemical properties of hemoglobin (polymerization in the deoxy form, impaired oxygen affinity)

Splenectomy – surgical removal of the spleen

Tonsillectomy – surgical procedure involving the removal of the tonsils

Transient ischemic attacks are transient cerebral ischemic episodes

Trophic ulcers – slow-healing skin defects resulting from impaired blood supply to the affected area of the skin

Chelator is a substance that forms a stable, nontoxic compound with a metal (in this case, iron) capable of being eliminated from the body

Chelation therapy is the therapeutic use of chelators

Cholelithiasis – formation of stones (calculi) in the gallbladder or bile ducts

Cholestasis is a pathological (abnormal) process associated with impaired synthesis (formation), secretion (release), and flow of bile or its individual components into the duodenum

Cholecystectomy – surgical removal of the gallbladder

Enuresis is urinary incontinence

Erythroblastopenia – a decrease in the number of erythroblasts in the bone marrow

ASPEN syndrome is a combination of sickle cell disease, priapism, exchange transfusion, and a neurological complication

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Sickle cell disease (SCD) is a group of conditions caused by specific mutations in the beta-globin gene that alter the physicochemical properties of hemoglobin (polymerization in the deoxy form, impaired oxygen affinity of hemoglobin). SCD includes sickle cell anemia (homozygosity for abnormal hemoglobin S (HbSS; resulting from the substitution of glutamic acid with valine at position 6 of beta-globin)) and other conditions resulting from the co-inheritance of abnormal HbS with other defects of the beta-globin gene that lead to a quantitative reduction in normal beta-globin (beta-thalassemia), (S-β-thalassemia), or another qualitative disorder of beta-globin [1–8].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Abnormal HbS polymerizes in the deoxy form, losing solubility. Hemoglobin polymerization depends on intracellular HbS concentration, the degree of hemoglobin deoxygenation, pH, and intracellular HbF concentration. HbS polymers interact with the erythrocyte membrane, changing the shape of erythrocytes to sickle-shaped. Sickled erythrocytes occlude the microvasculature, leading to vascular damage, organ infarctions, painful crises, and other symptoms associated with SCD [3–9].

Two pathological processes occur simultaneously in SCD: hemolysis and vaso-occlusion [3–9]:

• Hemolysis leads to anemia and functional nitric oxide deficiency, which in the long run causes vascular endothelial damage, the development of proliferative endotheliopathy, and complications such as pulmonary hypertension, priapism, and stroke.

• Vaso-occlusion causes acute and chronic tissue ischemia, manifesting as acute pain (pain crisis) and causing organ damage.

1.3 Epidemiology of the Disease or Condition

According to WHO data, more than 4 million people worldwide suffer from SCD, and 6 to 9 million patients with SCD are born annually in African countries alone [10]. About 80% of SCD patients are of African descent; SCD is also quite common in India and Arab countries, as well as among descendants of these populations living in other regions (North America, European countries, Great Britain). For instance, in the USA, SCD occurs with a frequency of 1 in 5,000 population, in France 1 in 2,500 population, and in Great Britain 1 in 2,000 population [10]. For the Russian Federation, SCD is a rare disease, with sporadic cases found mainly in regions bordering the Republic of Azerbaijan [6]. On average, SCD patients in developed countries survive to 30–40 years of age [10].

1.4 Features of Coding the Disease or Condition

D57 – Sickle-cell disorders

D57.0 – Sickle-cell anemia with crisis (HbSS disease with crisis)

D57.1 – Sickle-cell anemia without crisis

D57.2 – Double heterozygous sickle-cell disorders (HbSC, HbSD, HbSE disease, sickle-cell beta-thalassemia, etc.)

D57.3 – Sickle-cell trait

D57.8 – Other sickle-cell disorders

1.5 Classification of the disease or condition

Currently, SCD is classified based on the presence or absence of a crisis and the specific genotype [1–6].

• sickle cell anemia with crisis;

• sickle cell anemia without crisis;

• sickle cell disorders with crisis;

• sickle cell disorders without crisis;

• sickle cell beta-thalassemia with crisis;

• sickle cell beta-thalassemia without crisis.

1.6 Clinical presentation of the disease or condition

Pallor of the skin and mucous membranes, sometimes mild icterus, appear at 3–6 months of age and intensify with age.

Splenomegaly may be present in some patients older than 6 months, but in the majority, asplenia develops by 6–8 years of age due to vaso-occlusive crises.

Hepatomegaly may be present in patients during the first 10 years of life.

Pain syndrome of varying localization and intensity in patients older than 1 year due to vaso-occlusive crises.

Low-grade/febrile fever due to vaso-occlusive crises in patients older than 1 year.

Delayed physical and sexual development in childhood and adolescence.

The development of various SCD complications is accompanied by an expanded clinical presentation.

The main cause of mortality and disability in SCD patients, especially in childhood, is stroke, which occurs in 5–10% of children with SCD, while silent strokes occur in up to 20% of SCD patients under 20 years of age. The second major cause of disability and mortality in SCD is acute chest syndrome (ACS), which develops as a result of infection, pulmonary infarction, or a combination thereof, along with acute splenic sequestration [11–21]. Other causes of disability include lesions of the lungs, liver, kidneys, and eyes, priapism, avascular necrosis, osteomyelitis, and lower extremity trophic ulcers [11–21]. One of the main reasons for hospitalization in SCD is pain crises of any localization and intensity [1–8]. Life-threatening acute complications of SCD include fulminant sepsis, acute chest syndrome (ACS), acute splenic or hepatic sequestration, ischemic or hemorrhagic stroke, subarachnoid hemorrhage, acute kidney injury, multiple organ dysfunction syndrome, biliary obstruction syndrome (intrahepatic cholestasis), fulminant priapism, post-transfusion hyperhemolysis syndrome, acute ophthalmological complications, and osteonecrosis of major joints (e.g., hip, shoulder) [1, 2, 11–21].

As a result of repeated splenic vaso-occlusive crises, asplenia develops, which is accompanied by a sharp increase in the risk of death from infections, particularly pneumococcal [1–6, 22].

Stroke is one of the main complications of SCD, accompanied by significant patient disability. Patients who have suffered a stroke experience impaired cognitive function and disrupted social adaptation. Cooperative SCD studies have shown a predominant occurrence of stroke in patients with HbSS (4 times higher than in patients with HbSC, etc.), primarily at the age of 2–5 years. The incidence of stroke in the USA among patients with HbSS is 0.6 per 100 patient-years, reaching 11% of all SCD patients by age 20 [1–6, 8, 12, 18–21, 23].

In SCD patients, various cardiovascular abnormalities are very frequently observed regardless of age: cardiomegaly and a hyperactive precordium, systolic murmurs (in the majority of patients), and premature contractions (frequently present in adult patients). Physical performance is reduced to approximately half in adult patients with SCD and by 60 to 70 percent in children, which is associated with the severity of anemia [1–6, 24, 25]. Cardiomegaly and heart murmurs often raise the question of congestive heart failure. Myocardial contractility is normal, and overt congestive heart failure is rare, especially in children. When heart failure is present, it is often associated with secondary causes, such as fluid overload. Cardiac output is increased at rest and increases further with physical exertion [24–26]. ECGs often show non-specific abnormalities, such as signs of ventricular enlargement. At rest, the cardiac index is 1.5 times the normal value and increases more during physical exertion, which is not fully explained by Hb or oxygen content, thereby indicating an increase in myocardial oxygen consumption [1–6, 8, 12, 14, 24–26].

Older children often have increased left and right ventricular and left atrial chamber sizes, increased interventricular septum thickness, and normal myocardial contractility. These changes, except for the right ventricle, were inversely proportional to Hb and indicate left heart dilatation, which is also age-dependent. In the presence of homozygous $\alpha$-thalassemia-2, left ventricular dimensions were more normal, but wall thickness was increased. This difference was the result of higher Hb due to $\alpha$-thalassemia. Nevertheless, no improvement in exercise tolerance was noted, possibly due to the abnormal properties of sickle erythrocytes [24–26]. Pericardial effusion was present in 10% of patients, which also showed an inverse relationship with Hb [24].

Blood pressure in SCD patients is higher than expected for the degree of anemia severity, suggesting the presence of relative arterial hypertension [27, 28]. A small study showed a relationship between increased BP and stroke development. Survival decreases and the risk of stroke increases with elevated BP, suggesting the pathogenetic importance of "relative" arterial hypertension. Increased life expectancy, higher prevalence of sickle cell nephropathy, and consumption of a high-calorie, high-salt diet likely contribute to the increasing incidence of absolute hypertension in SCD patients. When added to the obvious risks of even relative arterial hypertension and the fact that lowering blood pressure in individuals without SCD can prevent the consequences of hypertension, it seems reasonable to consider antihypertensive therapy in SCD patients with borderline hypertension [27, 28].

Myocardial infarction in SCD patients is quite rare, and coronary artery occlusion is also extremely rare [29], suggesting that small vessel vasculopathy leads to cardiac involvement. SCD patients may experience myocardial ischemia, which must be ruled out when they present with chest pain [29, 30].

Adult SCD patients frequently experience sudden death, which is associated with cardiac conduction system dysfunction [30].

ACS is an acute onset disease characterized by fever (above 38.5^°C) and respiratory symptoms (shortness of breath, tachypnea, noisy breathing, wheezing, decreased breath sounds), accompanied by new infiltrative changes in the lungs on targeted chest X-ray (chest CT) [1–6, 31, 32]. Because the appearance of radiological changes may be delayed, the diagnosis is not established immediately. The main risk factor for developing ACS is the SCD genotype: most common in HbSS, and least common in S/$\beta$⁺-thalassemia [31, 33, 34]. ACS is the most frequent cause of surgical interventions and anesthesia in SCD patients [33]. Children have a higher incidence of ACS development, but a lower mortality rate (<2%) than adults (4–9%) [31, 33]. In HbSS patients, ACS episodes are associated with low HbF, high hematocrit, leukocytosis, and the absence of $\alpha$-thalassemia co-inheritance. In children, there is seasonality in the incidence of ACS: lower in summer, more frequent in winter when the probability of acute respiratory infections is high. In adult SCD patients, seasonality of ACS development is almost absent. ACS may occur with or without progressive respiratory failure, characterized by non-cardiogenic pulmonary edema and severe hypoxemia [31–34].

In a large clinical study [33, 35], among the causes that triggered the development of ACS were pulmonary fat embolism (16.2% of ACS cases; in older patients with low oxygen saturation, 44–77% of ACS cases) and infections (54% of ACS cases). The spectrum of infectious agents includes Chlamydia (13%), Mycoplasma (12%), various viruses (12%), and bacteria, including St. aureus, Str. pneumoniae, Haemophilus influenzae (8.2%).

The short-term prognosis of ACS with limited lung involvement and mild hypoxemia is good. There are reports linking frequent ACS episodes to the development of chronic lung disease [33], while an equal number of publications report no subsequent lung damage in patients with recurrent ACS [31, 33].

Bone marrow infarction and necrosis are known complications of SCD [36]. When the infarction is massive, the necrotic bone marrow and fat embolize the pulmonary vessels [35, 36]. Fat droplets can enter the systemic circulation, leading to fat embolism syndrome (FES) [37]. Thus, in addition to respiratory failure, patients develop multi-organ failure from emboli in organs such as the kidneys and brain. FES can affect patients even with a mild course of SCD. Risk factors for FES development [37] include the HbSC genotype, pregnancy, and prior glucocorticoid treatment. Clinical manifestations vary widely and depend on which organ is involved and to what extent. Initially, a painful crisis occurs with the rapid onset of fever, hypoxemia, azotemia, liver damage, altered mental status, or coma. Hematological features include progressive anemia, normoblastosis in the peripheral blood, thrombocytopenia, and DIC. FES is frequently suspected, but quite difficult to confirm. Indirect evidence of FES includes the presence of lipid-laden macrophages in bronchoalveolar lavage, fat inclusions in pulmonary microvascular cells, fat inclusions in the leukocyte mass of venous blood, or multiple foci of bone marrow necrosis on scans. Lung damage (TRALI/ALI, pulmonary fat embolism) often precedes or accompanies FES; thus, initiated transfusion therapy for hypoxemia in patients with ACS stops or prevents the development of FES [35–37].

Liver and biliary tract dysfunction is one of the most frequent complications of SCD [38]. Hepatobiliary complications can be divided into several categories: those related to hemolysis, caused by anemia and its transfusion therapy, consequences of sickling and vaso-occlusion, and diseases unrelated to SCD [38].

Chronic hemolysis, with its accelerated bilirubin turnover, leads to a high incidence of cholelithiasis [38, 39]. As a rule, due to hemolysis alone, the bilirubin concentration in SCD patients does not exceed 68 $\mu$mol/L, and the conjugated fraction is less than 10%. A marked increase in the unconjugated fraction has been registered in association with a genetic defect of the glucuronyltransferase system (Gilbert syndrome) [40, 41].

Ultrasound examination of patient populations has shown that the onset of cholelithiasis occurs between the ages of 2 and 4 years [42]. With age, the incidence of cholelithiasis increases, reaching 30% by age 18. The prevalence of this complication depends on patients' dietary habits (patients with a predominance of plant fiber in their diet less frequently have cholelithiasis) and the disease genotype. Xenobiotics, such as 3rd-generation cephalosporins, can crystallize in the gallbladder lumen, and differences in the use of such systemic antibacterial drugs may explain some geographical differences in the incidence of cholelithiasis. Co-inheritance of $\alpha$-thalassemia reduces the degree of hemolysis and, accordingly, the frequency of gallstone formation. Common bile duct obstruction is often incomplete because pigment stones are small, but they can still cause characteristic biochemical changes of cholestasis. Cholelithiasis may occur with or without pancreatitis [38, 39, 42–44].

Biliary sludge is a viscous material that does not produce acoustic shadowing on ultrasound and can be a precursor to gallstone formation. Certain systemic antibacterial drugs, such as ceftriaxone**, may contribute to sludge formation. Studies in patients with SCD show that sludge is frequently found alongside gallstones in the gallbladder, but the sludge itself may not necessarily progress to stone formation [42–44]. However, the follow-up period in such studies is short.

Fever, nausea, vomiting, and abdominal pain are frequent manifestations of many liver, intestinal, pancreatic, vertebral, pulmonary, and neurological diseases [45]. Table 1 presents a list of conditions that may present with the aforementioned symptoms at onset and are common in patients with SCD.

Table 1. Causes of abdominal pain (right upper quadrant) and abnormal liver function tests in biochemical blood analysis.

A thorough clinical evaluation is necessary to establish a definitive diagnosis. Liver and spleen scintigraphy may be useful, but its use is controversial due to a high rate of false-positive results and low positive predictive value. Nevertheless, it has a high negative predictive value. False-positive results may occur as a result of prolonged fasting, severe liver disease, extrahepatic obstruction, chronic cholecystitis, or drug-induced spasm of the sphincter of Oddi.

Several cases of progressive cholestasis have been described, characterized by right upper quadrant abdominal pain, extremely high bilirubin levels, a sharp increase in alkaline phosphatase activity, variable increases in hepatic transaminases, and frequently accompanied by renal failure, thrombocytopenia, and marked hypocoagulation. Mortality is due to uncontrolled bleeding and hepatocellular failure [46].

Splenic sequestration is the main cause of an acute, profound drop in hemoglobin, which frequently leads to a fatal outcome (one of the leading causes of death in children) [22, 47].

Acute splenic sequestration (ASS) develops as a result of erythrocyte trapping in the spleen, followed by a rapid drop in Hb (and a high risk of hypoxic shock). Diagnostic criteria for ASS include a rapid drop in Hb by $\ge$20 g/L from baseline, markedly pronounced reticulocytosis, and acutely developed splenomegaly. ASS can occur at any age starting from 5 weeks of life, most frequently between 3 months and 5 years, and is often triggered by a viral or bacterial infection. Common clinical manifestations of ASS include sudden weakness, pallor, tachycardia, tachypnea, and abdominal enlargement. Mortality in ASS is 20%. Prognostic factors for the development of ASS have not been determined. ASS develops most frequently and at an earlier age in patients with HbSS SCD, and less frequently in those with HbSC and S/β⁺-thalassemia (mean age 9 years) [47].

The kidneys in patients with SCD exhibit multiple structural and functional abnormalities throughout the nephron [48]. The renal medulla, the site of the renal tubules and blood vessels (often referred to as vasa recta), is characterized by hypoxia, acidosis, and hypertonicity, which promote HbS polymerization and, consequently, erythrocyte sickling, leading to rapid disruption of blood supply and, subsequently, function. With age, there is a sharp decrease in the number of blood vessels in this area; the remaining vessels are significantly dilated, spirally tortuous, and often end blindly. Table 2 summarizes all renal complications caused by SCD [48].

Table 2. Renal involvement in SCD.

Hyposthenuria—the inability to concentrate urine—is the most frequent renal complication of SCD, which develops in early childhood and manifests as enuresis. Impaired urinary concentration ability is often combined with nocturia [48, 49]. Due to the impaired ability to concentrate urine, patients with SCD are more sensitive to dehydration, a factor that triggers vaso-occlusion. Therefore, it is very important for patients with SCD to consume plenty of fluids to compensate for losses caused by hyposthenuria [49].

Nocturnal enuresis may be a manifestation of cerebral hypoxia resulting from proliferative endotheliopathy and can be one of the manifestations of "silent" strokes in patients with HbSS. If nocturnal enuresis persists in children older than 1 year, the child should be evaluated to rule out urinary tract pathology, fluid intake should be reviewed (fluid evenly distributed throughout the day), and parents should be counseled on the need to monitor the child's urination (waking the child at night for additional urination). If nocturnal enuresis cannot be resolved by 6 years of age, nocturnal sO₂ monitoring should be performed, additional room oxygenation recommended [1–5, 7, 8], and in the absence of a response to standard recommendations for managing nocturnal enuresis, therapy with desmopressin** should be considered once the child reaches 5 years of age or older [49].

Tubular dysfunction is common in patients with SCD [49]. Patients typically have a normal aldosterone and renin response. Primarily, there is incomplete distal renal tubular acidosis; the severity of urinary acidification impairment is partly related to the severity of hyposthenuria [49].

Impaired potassium excretion does not lead to hyperkalemia as long as renal function is preserved, but when patients use antihypertensive agents (ACE inhibitors, beta-blockers, and potassium-sparing diuretics), hyperkalemia may develop [1–5, 7, 8, 49].

Increased creatinine secretion leads to low serum creatinine levels and, consequently, an overestimation of glomerular filtration function in patients with SCD. The difference is up to 30% when estimating the glomerular filtration rate by inulin clearance. This feature must be taken into account when prescribing drugs whose primary route of excretion is renal [49].

Despite increased uric acid secretion, patients with SCD frequently have hyperuricemia and are predisposed to secondary gout [49].

Hematuria is a frequent complication of SCD that develops as a result of HbS polymerization and erythrocyte sickling in the renal medulla [1–5, 7, 8]. It may be a presenting sign of papillary necrosis or renal medullary carcinoma [49]. In most cases, blood loss originates from the left kidney; bilateral involvement is extremely rare.

Hematuria may also occur in HbS carriers (HbAS) [1–5, 7, 8, 49].

Acute kidney injury (AKI) develops in patients with SCD as one of the manifestations of acute multiorgan failure syndrome (AMFS) [1–5, 7, 8, 49]. This syndrome is characterized by the sudden onset of severe dysfunction in at least two major organ systems (e.g., kidneys, lungs, liver) during an acute painful vaso-occlusive crisis. The pathophysiology of AMFS is microvascular vaso-occlusion in target organs, leading to ischemia of the organ parenchyma and impaired function. AKI may accompany rhabdomyolysis.

Proteinuria, which may progress to nephrotic syndrome, is the most common manifestation of glomerular involvement in patients with sickle cell disease (SCD) [1–5, 7, 8, 49]. Furthermore, up to 40% of patients with SCD (HbSS) may progress to chronic kidney disease (CKD) [50]. ACE inhibitors can reduce pathological changes such as focal segmental glomerulosclerosis and decrease urinary protein excretion in patients with early manifestations of sickle cell nephropathy. Renal failure develops earlier in patients with HbSS than in those with HbSC. Predictors of CKD development in patients with SCD (HbSS) include arterial hypertension, proteinuria, increasing severity of anemia, and hematuria; in addition, a high risk of CKD is noted in patients with the "Central African" haplotype of the $\beta$^S-globin gene cluster.

Priapism is a persistent, spontaneous, painful erection [51]. The mean age of onset for this complication is 12 years, and by age 20, 89% of male SCD patients have experienced one or more episodes. The cause is vaso-occlusion of the penile venous drainage. Priapism is considered prolonged if it lasts for more than three hours, and short-term if its duration ranges from a few minutes to three hours and resolves spontaneously [1–5, 7, 8, 51]. Repeated episodes of priapism lead to fibrosis and impotence. Patients must be informed that a full bladder can provoke priapism, and therefore regular and frequent bladder emptying is necessary; prolonged sexual activity; illicit drugs and potent medications (e.g., cocaine, alcohol, testosterone**, psycholeptics, sildenafil); urinary tract infection, and urethral trauma [51].

Chronic hemolysis in SCD leads to bone marrow erythroid hyperplasia, which is accompanied by bone deformation, most noticeable in the skull. Impaired growth of the maxilla leads to protrusion of the incisors and malocclusion. In long bones, osteopenia predisposes patients to pathological bone fractures. Similar changes are observed in vertebral bodies, accompanied by compression fractures leading to flattening and kyphotic spinal deformity. Protrusion of the femoral head unilaterally or bilaterally in SCD patients is also explained by osteopenia secondary to erythroid hyperplasia [52].

Avascular necrosis of the humeral and femoral heads can occur with any SCD genotype. The humeral head is more frequently affected in older age groups. If pain persists in the shoulder and/or hip joint, an MRI of the affected joint with determination of the radiological stage of involvement is indicated [52, 53].

Bones and joints are the primary sites of pain during vaso-occlusive crises. Sudden infarction is accompanied by acute pain and other symptoms resembling osteomyelitis. Infarctions most frequently occur in the vertebrae, pelvic bones, and long bones (most commonly the humerus, tibia, and femur, listed in descending order of frequency), with distal segments being affected more often. Clinically, there is swelling, induration, and localized hyperthermia of the skin over the lesion, along with a decreased range of motion in the adjacent joint. Unlike osteomyelitis, fever is typically absent, low-grade fever occurs rarely, and a left shift in the leukocyte formula is extremely rare. There is no specific radiographic pattern, making differentiation from acute osteomyelitis very difficult [1–5, 7, 8, 52].

Dactylitis, or "hand-foot syndrome," is observed only in newborns and young children. One or all 4 extremities may be affected simultaneously. Clinical manifestations include pain in the metacarpal, metatarsal, and phalangeal bones of the hands and feet; swelling typically occurs on the dorsal surface of the hand and foot, extending to the digits. Radiologically, periosteal thickening and a "moth-eaten" appearance of the affected bone are noted. Symptoms usually resolve within 1–4 weeks without any sequelae [1–5, 7, 8, 54].

Lower extremity trophic ulcers are rare in children [1–6]. Trophic ulcers are typically bilateral and localized in the malleolar region. They can be painless or accompanied by intense pain. The pathogenesis is not fully understood; most likely, they result from impaired microcirculation due to sickled erythrocytes and low tissue oxygenation. The role of zinc deficiency in their development cannot be excluded [1–8]. Therapy with #hydroxycarbamide** or scheduled red blood cell transfusion therapy does not affect the incidence and severity of trophic ulcers.

Pregnancy complications in female patients with SCD (Table 3) [55].

Table 3. Pregnancy complications in female patients with SCD.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of SCD is established based on clinical manifestations and laboratory findings [1–8] that reveal abnormal hemoglobin and/or globin gene defects. Laboratory diagnostic methods for SCD include:

• complete blood count with reticulocyte count and morphological evaluation of erythrocytes;

• hypoxic screening test for sickled erythrocytes, hemoglobin electrophoresis, hemoglobin capillary electrophoresis (identification of hemoglobin types), high-performance liquid chromatography (quantification of hemoglobin type ratios) (methods are listed in order of increasing efficacy in detecting abnormal hemoglobin);

• DNA analysis of globin genes (identification of point mutations in the globin gene, detection of extended deletions of the alpha-globin locus)

2.1 Complaints and Anamnesis

• All patients with suspected or verified SCD are recommended to undergo a history taking and symptom assessment regarding blood and hematopoietic organ disorders during each visit to a hematologist, in order to identify symptoms characteristic of SCD and for differential diagnosis with other blood system diseases [1–8].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: the primary complaint is frequent episodes of pain of varying intensity and localization, accompanied by fever, pallor of the skin and mucous membranes; in early childhood, headaches with neurological manifestations may occur. Patients may also report enuresis, visual impairment, dyspnea, and jaundice.

History taking in SCD implies a thorough inquiry into the age of onset of the first symptoms, and the presence of family members (children or adults) with similar manifestations (disease).

During the physical examination (initial or follow-up), the following anamnestic data must be documented:

• clinical manifestations of SCD at the time of examination, specific types and severity of episodes (pain crises, malaise, etc.) that occurred since the last visit;

• presence/absence of headaches, priapism, abdominal pain, nocturnal enuresis, or any neurological manifestations that could indicate a potential stroke;

• compliance with recommendations for penicillin prophylaxis;

• compliance with vaccination recommendations and tolerance to previous vaccinations;

• methods used to relieve pain and fever at home;

• frequency and reasons for school absenteeism in children;

• cognitive function tests and academic performance;

• physical exercises performed by the child and/or participation in sports sections;

• planned travel (if applicable, and destinations).

2.2 Physical Examination

• All patients with suspected or verified SCD are recommended to undergo a visual inspection, palpation, and percussion for hematopoietic and blood disorders, along with nutritional status assessment during each visit to a hematologist, in order to identify clinical manifestations characteristic of SCD and for differential diagnosis with other blood system disorders [1–6].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: general physical examination involves the assessment of general physical condition, height and body weight, presence of secondary sexual characteristics appropriate for age, height, body weight, physical development, and nutritional status; degree of pallor and jaundice; liver and spleen size; presence of a heart murmur; and blood pressure.

SCD in early childhood has various manifestations. The very first clinical sign may be jaundice during the first few weeks of life. If hemolysis is not intense, jaundice is indicated by yellowing of the sclerae. Hepatomegaly is common in infants during the first months of life. Splenomegaly is frequently detected in SCD (all forms except SCA). In patients with long-standing anemia, a midsystolic murmur may be heard upon auscultation of the heart. In older children, delayed physical and sexual development becomes noticeable [1–8].

Patients with SCD often have a low nutritional status due to chronic inflammation caused by vaso-occlusion. Assessing nutritional status at each examination helps to objectively evaluate the severity of the patient's condition.

2.3 Laboratory Diagnostics

• All patients with suspected or confirmed SCD are recommended to undergo a complete (clinical) blood count with a differential leukocyte count (leukocyte formula), reticulocyte count, and a blood smear review to assess the patient's condition and analyze red blood cell, platelet, and leukocyte morphology abnormalities [1–6, 56, 57].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• All patients with suspected or confirmed SCD are recommended to undergo a general biochemical blood test every 3–6 months (measurement of total blood protein, determination of protein fractions by electrophoresis, total blood bilirubin, blood creatinine, blood urea, alanine aminotransferase activity, aspartate aminotransferase activity, lactate dehydrogenase activity, alkaline phosphatase activity) to assess liver and kidney function [58].

GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)

• All patients with suspected SCD are recommended to undergo the following tests to detect abnormal hemoglobin (in order of increasing detection efficiency) [1–6, 56, 57]:

- hypoxic test for sickling (only in children older than 2 years, since the presence of high amounts of HbF yields false-negative results);

- hemoglobin typing;

- quantitative assessment of hemoglobin fractions ratio.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• All patients with suspected SCD are recommended to test for point mutations in the globin gene and large deletions of the alpha-globin locus (to detect co-inherited deletion alpha-thalassemia) in order to identify genetic abnormalities that led to the development of SCD [1–6, 56, 57].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

2.4 Instrumental Diagnostics

• All patients with SCD are recommended to undergo duplex scanning of brachiocephalic arteries with color Doppler blood flow mapping annually for early detection of stroke [1–6, 59–62].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: in pediatric patients, if the blood flow velocity in the middle cerebral artery increases above 200 cm/s, the risk of stroke within the next 3 years increases by 40%, therefore annual duplex scanning of brachiocephalic arteries with color Doppler blood flow mapping is required; if the middle cerebral artery blood flow velocity is less than 170 cm/s, the examination is repeated in 1 year; if the velocity is 170–199 cm/s, the examination should be repeated in 1–4 months; if the result persists and the patient is older than 10 years, an MRI is required (children, especially under 10 years of age, will require anesthesia for an MRI scan).

• All patients with SCD starting from 2 years of age, if duplex scanning of brachiocephalic arteries is not feasible or if abnormalities in blood flow velocity in the major head vessels are detected, are recommended magnetic resonance imaging (MRI) of the brain with contrast or magnetic resonance angiography of intracranial vessels (pediatric patients will require anesthesia for the procedure) to detect cerebrovascular disorders [1–6, 59–62].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: the risk of stroke in children with SCD is 333 times higher than in healthy individuals; the risk of stroke in patients with altered brachiocephalic artery blood flow velocity increases by 3,000 times, and the risk of recurrent stroke in SCD is 70%. In SCD, the incidence of ischemic stroke is 54%, being highest in patients during the first 10 years of life and after 30 years. In the third decade of life, hemorrhagic strokes predominate. Regardless of age, 10–30% of patients with SCD have silent strokes detected on brain MRI, which significantly impair cognitive functions [209].

• All patients with suspected SCD are recommended bone MRI or (if MRI is unavailable) bone ultrasound to detect osteonecrosis and bone and joint abnormalities [1–6, 53, 63].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with SCD presenting with minor subarachnoid hemorrhages are recommended to undergo cerebral angiography to detect aneurysms or arteriovenous malformations for potential surgical intervention [1, 2, 64–68].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: pediatric patients will require anesthesia to undergo this procedure.

• All patients with SCD receiving regular red blood cell (RBC) transfusions are recommended cardiac and hepatic MRI using a special protocol (T2* sequence) to diagnose iron overload [69].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: T2* MRI is the most informative method for diagnosing iron overload.

2.5 Other Procedures

• All patients with SCD, starting from an early age, are recommended an annual ophthalmological examination and comprehensive eye exam (intraocular pressure measurement, ophthalmoscopy, and, if necessary, fluorescein angiography of the eye) to diagnose ophthalmological complications of SCD [1, 2, 7, 8, 70].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: patients with SCD who sustain eye or periorbital trauma must be examined by an ophthalmologist immediately, as they have a high risk of vision loss due to elevated intraocular pressure with anterior chamber hemorrhage (hyphema).

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The goal of treatment is to ensure normal growth and development of the child, preserve working capacity in adolescence and adulthood, and ensure a good quality of life for the patient.

3.1 Conservative Treatment

• All patients with SCD older than 2 years who experience severe pain crises requiring hospitalization 3 or more times per year or 2 or more episodes of acute chest syndrome are recommended pharmacological stimulation of HbF synthesis with #hydroxycarbamide** orally at a dose of 15–35 mg/kg/day (rounded up to the nearest whole capsule) daily on a continuous basis [1, 2, 67, 71–73, 3–7, 64–66, 67].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: continuous long-term administration of #hydroxycarbamide** provides 90% of patients with a substantial increase in HbF levels, which is sufficient to significantly improve the course of SCD.

Hematological response criteria:

1. complete – Hb >100 g/L, absence of pain crises and other SCD complications;

2. partial – Hb 85–100 g/L, absence of significant pain crises and other SCD complications;

3. no response – Hb <85 g/L, frequent pain crises of varying intensity, and possible presence of other SCD complications.

#Hydroxycarbamide** is excreted by the kidneys, therefore patients with impaired renal function require more careful monitoring of the #hydroxycarbamide** dose.

Patients receiving #hydroxycarbamide** must use adequate contraception. If a decision is made to conceive a child, #hydroxycarbamide** should be discontinued at least 1 month prior to conception [1, 2, 74–76]. There are case reports where #hydroxycarbamide** was not discontinued and was taken by patients throughout pregnancy with no fetal malformations observed. Methods of choice may include oral hormonal contraceptives (ATC code G03A) or parenteral (intramuscular) systemic hormonal contraceptives – progestins (ATC code L02AB), and barrier contraception [1, 2, 77]. The use of intrauterine devices is not recommended due to the high risk of severe complications associated with SCD [1, 2, 77].

3.2 Red Blood Cell Transfusion Therapy

Red blood cell transfusions are an effective treatment for acute, potentially life-threatening cases of anemia and severe vaso-occlusive crises. The transfusion regimen depends on the treatment plan and the complications that prompted the initiation of transfusion therapy. For regular (chronic) donor red blood cell (RBC) transfusions, it is advisable to place a single- or double-lumen tunneled catheter or implant a venous port system.

In 18% of cases, transfusions in patients with SCD are complicated by alloimmunization; to reduce this risk, it is necessary to transfuse RBC units compatible for blood group, Rh factor, Kell antigen, and rare factors (minor blood groups A-1, A-2, D, Cc, E, Kell, Kidd, Duffy [full extended RBC phenotype and genotype: C, c, D, E, e, K, k, Jka, Jkb, Fya, Fyb, Kpa, Kpb, MNS, Lewis]), with leukocyte depletion [209].

• Patients with SCD are recommended simple low-volume red blood cell transfusion (<7 mL RBC/kg, target Hb 100–110 g/L) in the following clinical situations [78–83]:

- acute chest syndrome;

- organ dysfunction of any kind;

- splenic or hepatic sequestration;

- sepsis or malaria;

- refractory painful vaso-occlusive crisis;

- acute anemia with clinical manifestations of anemic syndrome;

- preoperative preparation.

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• Patients with sickle cell disease (SCD) are recommended volumetric (exchange, replacement) red blood cell transfusion (the patient's blood HbS concentration should not exceed 30%, target Hb 120-130 g/L) in the following clinical situations [78–83]:

- stroke;

- recent complete hearing loss;

- central retinal artery thrombosis;

- preparation for major surgical interventions (chest, heart, eyes, etc.);

- acute refractory priapism.

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• Patients with SCD are recommended chronic regular leukoreduced red blood cell transfusions with individual matching (the patient's blood HbS concentration should not exceed 30%, target Hb 120-130 g/L) in the following clinical situations [78–83]:

- cerebral vasculopathy;

- recurrent severe acute chest syndrome and/or severe painful (vaso-occlusive) crisis;

- chronic organ failure: kidneys, heart, lungs, liver;

- pulmonary hypertension;

- severe growth retardation;

- 3rd trimester of pregnancy;

- psychosis;

- severe chronic anemia unresponsive to #hydroxycarbamide** therapy.

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• In patients with SCD who develop hyperhemolysis syndrome, #methylprednisolone** pulse therapy is recommended : children 15 mg/kg per day, adults 500-1000 mg/day, IV drip, for 3-5 days in combination with normal human #immunoglobulin** (IV administration – ATC code J06BA02) at a total course dose of 2 g/kg IV divided over 3-5 days [84–86, 214]

For children, Level of Recommendation B (Level of Evidence – 2)

For adults, Level of Recommendation C (Level of Evidence – 4)

Comments: the incidence of delayed hemolytic transfusion reactions (hyperhemolysis syndrome) in patients with SCD is 4-22%, which is significantly higher than in other diseases. When hyperhemolysis syndrome develops, alloantibodies cannot be detected in some cases. Hyperhemolysis syndrome is regarded as a life-threatening acute hemolytic complication of SCD.

• Patients with SCD older than 2 years, following 10-15 transfusions of individually matched leukoreduced (leukodepleted) red blood cell concentrates, upon the development of chronic transfusion iron overload (serum ferritin of 1000 µg/L or more), are recommended chelation therapy with deferasirox** (dispersible tablet formulation – initial dose 30 mg/kg/day orally daily, subsequently increased or decreased in steps of 5 mg/kg/day depending on serum ferritin; film-coated tablet formulation – initial dose 7-24 mg/kg/day orally daily, subsequently increased or decreased in steps of 3.5 mg/kg/day depending on serum ferritin concentration) [87].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: chelation therapy is considered adequate when serum ferritin is maintained in the range of 800-1000 µg/L; chelation therapy is discontinued when a serum ferritin concentration of 600 µg/L is reached.

During chelation therapy, it is necessary to perform:

1. Serum iron test, total iron-binding capacity (TIBC) test, transferrin saturation (TSAT) test, serum ferritin test

1. every 3 months during dose titration of the chelator, then every 6 months;

2. assessment of nephron function by creatinine clearance (Rehberg's test) before starting chelation therapy, monthly during the first 3 months at the dose titration stage, then after 3 months, and subsequently every 6-12 months;

3. complete urinalysis (proteinuria) weekly during dose titration, then monthly;

4. liver transaminase activity (panel of tests to assess hepatocellular injury (cytolysis grade));

5. T2* MRI to assess hepatic and myocardial iron overload once a year.

3.3 Hematopoietic Stem Cell Transplantation

• Patients with SCD younger than 17 years who have a related HLA-compatible donor and develop one of the SCD complications (stroke [or MRI evidence of stroke without clinical manifestations], cerebral vasculopathy with cognitive decline, severe or recurrent acute chest syndrome, stage 1-2 chronic respiratory failure, 3 or more painful [vaso-occlusive] crises requiring hospitalization per year over the last 3-4 years) are recommended hematopoietic stem cell transplantation (HSCT) [1, 2, 88–90].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: it has been shown that after related HLA-compatible HSCT, SCD-free survival is 80-92%, and mortality, mainly from chronic GVHD, is 5-10% [90–92].

• Patients with SCD are not recommended HSCT in the following cases [90]:

- Karnofsky performance scale <70%;

- moderate or severe portal fibrosis;

- moderate or severe impairment of glomerular renal function;

- severe intellectual impairment;

- multiple epiphyseal avascular necrosis;

- stage 3-4 chronic respiratory failure;

- cardiomyopathy;

- HIV infection;

- the donor is a patient with hemoglobinopathy.

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

3.4 Surgical treatment

Patients with SCD may require surgical interventions both for the treatment of SCD complications and for conditions unrelated to SCD. The risk of complications and the risk of death from anesthesia in such patients are significantly higher than in the general population, primarily due to the presence of anemia, the ability of red blood cells to sickle and occlude the lumen of small vessels and capillaries, the presence of chronic organ damage in some patients, the worsening of existing hypoxia, and finally the effect of asplenia. The risks are highest in patients with HbSS and S/β⁰-thalassemia [1, 2, 66, 67, 93, 3–8, 64, 65]. Many clinical studies have been conducted aimed at reducing the risk of surgical interventions and anesthesia. The incidence of postoperative complications increases with the patient's age (~1.3 for every 10 years of life) [1, 2, 64–67, 93, 94]. Complications develop more frequently in patients who undergo regional anesthesia than general anesthesia [1, 2, 93, 94]. Adenotomy and tonsillectomy in patients with SCD are regarded as high-risk surgical interventions due to blood loss, inability to drink, and fluid loss [1, 2, 64–67, 93, 94].

During preoperative preparation, attention must be paid to hematocrit, peripheral perfusion, and oxygen status [1, 2, 64–67, 93–96]. At least 8 hours before surgery, preoperative fluid administration (hemodilution) and red blood cell transfusion are required regardless of the surgical risk level: for low risk, a simple (low-volume) transfusion to maintain Hb ~100 g/L; for moderate and high risk, an exchange transfusion (reducing HbS concentration to less than 30%) [1, 2, 64–67, 93].

Intraoperatively, it is necessary to monitor blood pressure, heart rate and rhythm, oxygenation, and temperature (prevention of hypothermia) throughout the entire surgical procedure [1, 2, 64–67, 93, 94].

Postoperative management involves providing oxygen therapy with blood gas monitoring (sO₂), hydration, and respiratory support/therapy [1, 2, 64–67, 93, 94].

Frequent surgical interventions in SCD include adenotonsillectomy, splenectomy, cholecystectomy (usually laparoscopic), joint replacement, placement of a central venous cuffed catheter, and implantation of a subcutaneous venous port system [1, 2].

• Patients with SCD with a confirmed aneurysm or arteriovenous malformation are recommended surgical treatment (aneurysm excision or removal of the arteriovenous malformation) [1, 2, 64–68].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with SCD with retinal detachment or extensive vitreous hemorrhage are recommended surgical intervention – vitrectomy [1, 2, 70].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: although modern vitreoretinal microsurgery can improve vision for many patients with advanced stages of sickle cell retinopathy, it should be emphasized that the surgery carries a substantial risk of intraoperative and postoperative complications, including severe ocular ischemia, recurrent hemorrhage, and elevated intraocular pressure. To reduce such risk, partial exchange blood transfusion must be performed prior to surgery (HbA should constitute at least 50-60% of the patient's circulating blood).

• Patients with SCD with central retinal artery occlusion are recommended emergency intervention (no later than 1 hour from onset) – oxygen therapy combined with rapid intraocular pressure reduction (surgical and therapeutic) [1, 2, 70].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• Patients with SCD with vision loss due to hemorrhage or retinal detachment are recommended emergency surgical intervention (no later than 48 hours from onset) [1, 2, 70].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• For patients with sickle cell disease (SCD), when indicated, laparoscopic cholecystectomy with endoscopic retrograde cholangiopancreatography is recommended [1, 2, 95, 96].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: the indication for cholecystectomy in SCD is the development of cholelithiasis; laparoscopic cholecystectomy is the standard approach for a well-prepared patient. An aggressive approach offers the advantage of reducing the risk of complications from cholelithiasis, as well as ruling out gallbladder disease in the differential diagnosis of right upper quadrant abdominal pain.

3.4 Prevention of SCD Complications

• In patients with SCD who develop fever of unknown origin, a rapid response and aggressive treatment are recommended, including [66, 97–99]:

- hospitalization if body temperature rises above 38.5 °C;

- a baseline evaluation including: complete blood count, urinalysis, chest CT (or targeted chest radiography if CT is unavailable), acid-base balance and blood gas analysis, blood cultures for sterility, microbiological culture of tonsillar and posterior pharyngeal swabs for aerobic and facultatively anaerobic microorganisms, and urine culture for bacterial pathogens using automated inoculation;

- immediate (prior to obtaining test results) parenteral administration of systemic antibacterial drugs if the child exhibits symptoms of intoxication and/or a fever above 40.0 °C, or in children without symptoms of intoxication and with a temperature below 40.0 °C in the following clinical situations:

§ changes in sO₂ or infiltrative changes on chest radiography;

§ leukocyte count greater than 30×10⁹/L or less than 5×10⁹/L;

§ platelet count less than 100×10⁹/L;

§ hemoglobin less than 50 g/L;

§ history of sepsis;

- lumbar puncture with microbiological culture of cerebrospinal fluid for aerobic and facultatively anaerobic opportunistic microorganisms if the patient exhibits symptoms of intoxication with meningeal signs;

- children may receive treatment in a day hospital if they have no intoxication at a temperature below 40°C, have never had sepsis, chest CT (if unavailable - chest X-ray) or acid-base status and blood gases without abnormalities, borderline white blood cell count, platelet count and hemoglobin; they may be discharged for outpatient follow-up after administration of parenteral antibacterial therapy active against Streptococcus pneumoniae and Hemophilus influenzae (e.g., ceftriaxone** 75 mg/kg/day), provided that children remain clinically stable for 3 hours after drug administration, the regional endemic Streptococcus pneumoniae is susceptible to the prescribed drug, the parents are trained to monitor the patient with SCD, clearly follow the physician's recommendations, and the treatment prescribed in the day hospital will be continued on an outpatient basis at the place of residence.

- documented bacteremia must be treated parenterally for 7 days, and children with meningitis must receive at least 14 days of therapy.

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: after 3 months of life, with a significant decrease in HbF, there is a risk of developing splenic hypofunction with increased susceptibility to certain life-threatening bacterial infections (sepsis, meningitis, etc.). Studies conducted in the USA show that in HbSS, the incidence of severe bacterial infections, including meningitis and sepsis, increases sharply during the first six months of life, and in HbSC and S-β⁺-thalassemia during the first 2 years of life [1–5, 100–106].

Infection prevention (penicillin prophylaxis and vaccination) plays an essential role, so it is necessary to monitor the accuracy and timeliness of its implementation regardless of the patient's age.

Febrile patients with SCD should be evaluated and managed considering functional asplenia. This means that such patients must undergo a physical examination, complete blood count, blood cultures for sterility and/or microbiological cultures of tonsillar and posterior pharyngeal swabs for aerobic and facultatively anaerobic microorganisms and/or urine cultures for bacterial pathogens using automated inoculation, chest CT (or chest X-ray), and initiation of empiric antibiotic therapy in the shortest possible time. Children with SCD often present with low-grade fever, while the risk of death from undiagnosed Streptococcus pneumoniae sepsis is colossal.

• Regular sanitization of infection foci (oral cavity, tonsils, adenoids, paranasal sinuses, urinary system) is recommended for all patients with SCD [1, 2].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: foci of chronic infection typically provoke the development of severe vaso-occlusive crises and can be a cause of sepsis.

• For patients with SCD and elevated blood homocysteine concentrations, the administration of "folic acid and its derivatives" (ATC code B03BB) is recommended to correct these levels [1, 2, 113–115].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

• All patients with SCD are recommended to receive vitamin D and its analogs (cholecalciferol**) at a dose of 500 IU/day from 4 weeks of age to adolescence and 3000 IU/day for adult SCD patients, sufficient sun exposure, and an adequate calcium intake in their diet to prevent vitamin D deficiency [1, 2, 9, 10, 69-74, 190-192].

LoR CLoE 5 Level of Recommendation C (Level of Evidence – 5)

• For patients with SCD with no signs of puberty by the age of 14 years in girls and 14.5 years in boys, an initial consultation (examination) with an endocrinologist is recommended to address the need for hormone replacement therapy [1, 2, 7, 8, 64–68].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: patients with HbSS experience a 2–3 year delay in puberty, while patients with HbSC experience a ~6-month delay. Skeletal maturation delay during puberty prolongs the growth period of long bones, allowing an acceptable final height to be reached, albeit with a time delay. If girls aged 14 and boys aged 14.5 show no signs of puberty, an endocrinological evaluation is required to determine the need for hormone replacement therapy [1, 2, 9, 10, 69-74]. If the patient receives regular packed red blood cell transfusions, pituitary and/or gonadal dysfunction may result from iron overload [1, 2, 9, 10, 69-74].

• All patients with SCD presenting with priapism are recommended #leuprorelin** injections (a gonadotropin-releasing hormone analog that suppresses the hypothalamo-testicular axis and testosterone production) at 7.5 mg intramuscularly, along with long-term oral #hydroxycarbamide** therapy at a dose of 15–35 mg/kg/day (rounded up to the whole capsule) daily and continuously to prevent recurrent episodes of priapism [1, 2, 7, 8, 64–68, 118].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: adolescents and young adults with SCD may develop priapism in the morning hours (recurring episodes lasting 2–4 hours that resolve spontaneously, or a severe attack lasting more than 4 hours); adolescents and adult SCD patients should be informed that if priapism signs persist for 2 hours or more, they must seek emergency medical care. To relieve mild symptoms and prevent the development of severe priapism, patients should always empty their bladder before sleep, take a warm bath or shower, and take paracetamol** or ibuprofen** for pain relief. Patients must be informed about the risk of impotence as an outcome of severe priapism episodes [210].

3.5 Prevention of CNS Injury

In addition to changes in middle cerebral artery blood flow velocity, risk factors include [1, 2, 7, 8, 119–122]:

- transient ischemic attacks (transient cerebrovascular accidents);

- low hemoglobin levels;

- frequency and time elapsed since the onset of acute chest syndrome;

- elevated systolic blood pressure.

For children in their first two years of life, high-risk factors for ischemic stroke include dactylitis, severe anemia, and leukocytosis [1, 2, 7, 8, 119–122].

Other clinical and laboratory indicators of ischemic stroke risk include a history of stroke in a sibling, subtle neurological abnormalities, severe anemia, marked leukocytosis, specific β^S-haplotypes, and the absence of α-globin gene deletions [1, 2, 7, 8, 119].

Approximately 13% of children (up to 20% of patients under 20 years of age) with sickle cell disease (SCD) have "silent" brain injury; according to MRI, lesions are predominantly localized in the frontal and parietal lobes within the cortical, subcortical, and border zones. These lesions are associated with low neuropsychological test scores. An increased risk of ischemic stroke has been proven in children with abnormal MRI findings [1, 2, 7, 8, 119]. The presence of these lesions on MRI requires screening the child for learning disabilities and cognitive impairment, as well as evaluating cerebral vessels for the timely initiation of primary stroke prophylaxis. A detected "silent" brain injury in a child requires a reassessment of the medical history to identify previously unnoticed symptoms, as well as a review of clinical and laboratory risk factors for stroke. The incidence of stroke in children with abnormal MRI and TCD, as well as the risks and benefits of prophylaxis with chronic packed red blood cell transfusions, have not been studied. Studies are currently underway to investigate the efficacy of regular packed red blood cell transfusions for "silent" strokes.

• In SCD patients with an increased middle cerebral artery blood flow velocity up to 200 cm/s, regular (chronic) packed red blood cell transfusions are recommended to prevent the development of ischemic stroke [1, 2, 7, 8, 120, 121, 209, 211].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: chronic packed red blood cell transfusions maintaining HbS levels below 30% of total Hb significantly reduce the risk of recurrent stroke [1, 2, 7, 8, 120, 209, 211]. Chronic packed red blood cell transfusions should be continued until the child is 18 years old, but for at least 5 years from the start of transfusions [1, 2, 7, 8, 120].

Some patients, despite adequate reduction of HbS through packed red blood cell transfusions, develop recurrent episodes of CNS injury. In this case, it is necessary to determine the patient's blood HbS level (to verify that the patient's transfusion program was adequate) and to identify the cause of ischemia. Other risk factors besides SCD-induced vasculopathy must be kept in mind: elevated homocysteine levels and other conditions accompanied by hypercoagulability. Elevated homocysteine can be reduced by taking folic acid** (in adult patients, in accordance with the package insert). Evidence suggests that some patients with SCD have elevated antiphospholipid antibodies and protein C and S deficiency [1, 2, 7, 8, 120, 123–125].

• In children with SCD and hypercoagulability, anticoagulant therapy with warfarin** is recommended for the prevention of venous thrombosis and embolism [126, 127].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• In SCD patients who have suffered a cerebral infarction/ischemia, hematopoietic stem cell transplantation is recommended to prevent recurrent attacks [1, 2, 7, 8, 88, 89, 92].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• In adult patients with SCD, prevention and treatment of ischemic stroke are recommended in accordance with relevant clinical guidelines [1, 2, 7, 8].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• In adult patients with SCD presenting with a transient ischemic attack (TIA), prevention of ischemic stroke with antithrombotic agents or warfarin** is recommended [1, 2, 7, 8, 128–130].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: drugs for secondary stroke prevention in adult patients with SCD are presented in Table 5 [131, 132].

Table 5. Drugs for secondary stroke prevention in adult SCD patients.

As an alternative in adult patients with SCD, chronic (regular) packed red blood cell transfusions can be used for secondary prevention of ischemic stroke, similar to pediatric practice [1, 2, 7, 8, 82]. Surgical interventions may be used in certain cases to correct Moyamoya syndrome [1, 2, 7, 8].

• In adult patients with SCD, secondary prevention of ischemic stroke with acetylsalicylic acid** or warfarin** is recommended [1, 2, 7, 8, 128–130].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

No specific rehabilitation measures have been developed for patients with SCD. Regardless of age and ongoing therapy, patients with SCD may attend preschools and schools, stay in recreation camps, and engage in physical education and sports. Patients who have suffered a stroke, especially a recurrent one, will require social rehabilitation.

It is beneficial for patients with SCD to engage in physical education and sports, but it is essential to remember the need to keep warm (after intensive physical exercise, the child must be covered/dressed warmly to prevent hypothermia; swimming in cool/cold water is not recommended) and to monitor adequate fluid intake by the child to prevent dehydration, which will help prevent vaso-occlusive crisis.

5. Prevention and Dispensary Observation

Following diagnosis, selection of treatment tactics, and dose titration, the patient is transferred to outpatient follow-up care by a pediatrician (or a hematologist, if such a position exists) at the patient's place of residence. Therapy is administered on an outpatient basis, long-term/lifelong. Patients and their family members must be thoroughly informed about the nature of the disease, potential complications of both the disease itself and the therapy administered, and trained in personal hygiene rules and pain management.

• All patients with sickle cell disease are recommended lifelong follow-up by a hematologist and a pediatrician/general practitioner, involving other specialists as needed [1, 2, 64–68].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: most patients require outpatient treatment and/or prevention of severe manifestations of the disease or its complications; inpatient treatment is required extremely rarely.

Required measures for clinical follow-up (dispensary observation) are presented in Table 6.

Table 6. Required medical services during clinical follow-up [1, 2, 7, 8, 65–68, 133]

Vaccine prophylaxis (Table 7) [1–5, 69–74, 177–182, 212]. Preventive vaccination for patients with severe congenital blood disorders is carried out in accordance with these clinical guidelines (Table 7) [1–5, 69–74, 177–182].

• All patients with severe congenital blood disorders are recommended to receive pneumococcal vaccination during the first year of life – adsorbed conjugated polysaccharide pneumococcal vaccine**, starting at 2 years of age (24–27 months) and subsequently every 5 years with the pneumococcal vaccine** [1–5, 69–74, 177–181].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

• All patients with severe congenital blood disorders are recommended to receive hepatitis B vaccination in accordance with the national immunization schedule [1–5, 69–74, 177].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• All patients with severe congenital blood disorders are recommended to receive annual influenza vaccination [1–5, 69–74, 177].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• All patients with severe congenital blood disorders are recommended to receive COVID-19 vaccination, which is as safe and effective as in healthy individuals [212].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Table 7. Recommended vaccine prophylaxis schedule for patients with severe congenital blood disorders. Grade of recommendation C (Level of evidence – 5) [1–5, 69–74, 177–182, 212]

* if vaccination was not performed in the first year of life;

** every 10 years of life thereafter;

*** every 5 years of life thereafter.

• All young children with sickle cell disease (SCD), starting from 2 months of age, are recommended to receive beta-lactamase-sensitive penicillins (#Benzathine benzylpenicillin + Benzylpenicillin procaine) at a dosage regimen of 1.2 million IU intramuscularly every 3 weeks or #erythromycin at a dosage regimen of 20 mg/kg/day divided into two doses [1–5, 69–74, 174–176].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: sanation of infection foci (oral cavity, tonsils, adenoids, paranasal sinuses, urinary system) is recommended for all patients with SCD [1–5]. Foci of chronic infection typically provoke the development of severe vaso-occlusive crises and can be a cause of sepsis.

• SCD patients, regardless of age, require a high-calorie diet, which significantly improves growth rates [1, 2, 9, 10, 69–74, 183–185].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: patients with SCD, especially children, exhibit growth retardation, low nutritional status, and delayed skeletal and sexual maturation. Growth retardation becomes noticeable starting from 6 months of age. This is believed to be associated with accelerated metabolism in SCD, decreased appetite (sometimes progressing to anorexia) during pain crises, and reduced gastrointestinal nutrient absorption [1, 2, 9, 10, 69–74, 183–185]. Numerous studies of SCD patients have shown a decrease in adipose tissue mass in adolescence and a decrease in non-fat body mass components in all patients regardless of age, with significantly reduced muscle mass and body protein reserves [1, 2, 9, 10, 183–185].

• All patients with SCD aged 4 to 18 years are recommended to receive zinc sulfate supplementation in their diet [1, 2, 9, 10, 69–74, 186].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: it has been shown that zinc sulfate supplementation improves physical development rates and reduces the number of infectious episodes [1, 2, 9, 10, 69–74, 186].

Transfer to the adult medical care network should be gradual. Planning and preparation for transferring the patient to adult care should begin when the child reaches 13–14 years of age [1, 2]; a detailed summary of all patient medical records should be prepared by 15–16 years of age [1, 2]; a hematologist from the adult/adolescent center should participate in patient discussions starting from 13–14 years of age, which ensures continuity of medical care and familiarizes the child with the operation rules of the center that will subsequently monitor them [1, 2].

6. Organization of Medical Care

Indications for hospital admission to a medical organization:

1. planned hospitalization in a day hospital (short-term treatment hospital):

a. red blood cell suspension (mass) transfusions

2. planned hospitalization in an inpatient hospital:

a. preoperative preparation

b. 3rd trimester of pregnancy

3. emergency hospitalization in a day hospital (short-term treatment hospital):

a. moderate to severe pain syndrome (refractory painful vaso-occlusive crisis)

4. emergency hospitalization in an inpatient hospital:

a. acute chest syndrome

b. splenic or hepatic sequestration

c. sepsis or malaria

d. acute anemia with clinical manifestations of anemic syndrome

e. stroke

f. acute refractory priapism

Indications for patient discharge from a medical organization

1. achievement of target hemoglobin

2. relief of pain syndrome and resolution of complications or comorbid conditions

7. Additional Information

7.1 Pain Crises in SCD

Pain in SCD can be classified into acute and chronic [1–7, 64–68, 134–154]. Conditions associated with pain crises are presented in Table 8. Acute pain is the most common in SCD; its onset is sudden without prodromal signs, its duration is limited from several hours to several days, its intensity varies significantly from moderate to excruciating, pain can recur, and its localization may vary. Chronic pain is pain lasting 3–6 months or longer, difficult to differentiate from frequently recurring acute pain (e.g., bone pain), and can be physically and psychologically debilitating. The involvement of sensations, emotions, memory, and perception creates additional challenges in its management. Acute pain often overlays chronic pain, and frequent episodes of acute pain may mimic chronic pain. Neuropathic pain is insufficiently characterized in SCD; it arises as a result of nerve structure infarctions, compression, the action of endotoxins, and/or iron overload.

Table 8. Acute and chronic pain and complications of SCD [1, 2, 67, 68, 138–140, 142, 144, 146, 148, 3–7, 64–66].

Pain intensity assessment must take into account the patient's age, developmental level, functional status, cognitive function, and emotional state. All these factors must also be considered when choosing therapy. Pain relief should be prompt and maximally effective [1, 2, 67, 68, 134–141, 3, 142, 4–7, 64–66]. A special algorithm (Appendix B2) is used to assess pain intensity and characteristics [1, 2].

Parent and patient education regarding the pathophysiology of SCD and the causes of pain plays a major role in pain management [1, 2, 140–142, 64–68, 137–139]. The availability of accessible day hospitals for patients is crucial for managing severe pain episodes, as it reduces the number and duration of inpatient hospitalizations [1, 2, 134, 136, 139, 140].

Factors provoking pain crises must be avoided, such as: exposure to low temperature (cooling), exposure to high temperature (overheating), prolonged intense physical exertion, dehydration, ascending to altitudes above 1,500 m above sea level, tobacco smoking, and alcohol consumption [1, 2, 140–142, 64–68, 137–139].

Non-pharmacological pain relief methods are effective (warming massage, warm/hot shower or bath, reflexology, distraction techniques (games, including computer games, video; TV) [1, 2, 140–142, 64–68, 137–139].

• To assess pain intensity in children, it is recommended to use the Visual Analog Scale for pain assessment (see Appendix G1 of these guidelines) or other multidimensional scales for acute or chronic pain [1, 2, 140–142, 64–68, 137–139]. Maintaining a patient diary also helps in assessing pain at home.

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Pain management in patients with SCD should be carried out in accordance with relevant clinical guidelines.

7.2 Transient Red Cell Aplasia

Transient red cell aplasia (TRCA) develops as a result of parvovirus B19 infection (parvovirus B19 also causes erythema infectiosum, known as "fifth disease"). Aplasia is the result of the direct cytotoxic effect of the parvovirus on erythroid precursors; precursors of other cell lines may also be affected to some extent. Patients may present with progressive headache, weakness, dyspnea, more severe anemia than usual, and a profound decrease in reticulocyte count (usually less than 1% or 10 × 10⁹/L). Fever, signs of upper respiratory tract infection, and/or gastrointestinal symptoms may also occur. Skin rashes have no specific characteristics. Reticulocytopenia appears around the 5th day of infection and lasts for 5–10 days. Worsening of anemia occurs shortly after reticulocytopenia, with Hb dropping to 39 g/L. The first sign of recovery from infection is marked reticulocytosis, which, while profound anemia persists, is sometimes misdiagnosed as hyperhemolysis syndrome. Recovery is typically accompanied by the appearance of a large number of normoblasts in the peripheral blood (more than 100 per 100 leukocytes). The diagnosis of TRCA is confirmed by elevated levels of anti-parvovirus B19 IgM in the blood. Recovery from parvovirus B19 infection is accompanied by the appearance of protective IgG titers, preventing reinfection throughout the patient's life.

Controlled studies on TRCA therapy have not been conducted. Some patients recover spontaneously.

Although most adults have acquired immunity to parvovirus B19, healthcare workers who are susceptible and in contact with SCD patients are at high risk of nosocomial infection with erythema infectiosum. Infection acquired during the second trimester of pregnancy can lead to hydrops fetalis and stillbirth, which is why isolation precautions are necessary for staff in the event of pregnancy.

• Patients with severe SCD are recommended red blood cell suspension transfusions [1, 2, 64–68].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: transfusions are most frequently required in patients with HbSS, and least frequently in those with HbSC.

• Patients with SCD are recommended therapy with #normal human immunoglobulin** in the pharmaceutical form of "solution for infusions" (IVIG**) at a course dose of 2 g/kg IV, divided over 3–5 days [155].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

7.3 Ocular Manifestations of SCD

Peripheral retinal vaso-occlusion can be detected as early as 20 months of age, and clinically significant retinal damage is usually observed at 15–30 years of age. Sickle cell retinopathy most frequently and early develops in HbSC patients, but is also quite common in HbSS and S-β-thalassemia patients. Stages IV and V retinopathy are more frequently diagnosed in HbSC than in HbSS patients. Less severe systemic involvement in SCD in patients with HbSC and S-β-thalassemia is paradoxically accompanied by more severe ocular damage than in HbSS. The risk of proliferative retinopathy increases with age [1–6].

Upon detection of proliferative retinopathy, the patient should be referred to a specialized ophthalmology center.

• For the diagnosis of proliferative retinopathy in patients with SCD, recommended are an initial ophthalmologist examination with a dilated pupil using a wide-field indirect ophthalmoscope (slit lamp) (ophthalmoscopy), and assessment of retinal blood flow by fluorescence angiography (fluorescence angiography of the eye) [1, 2, 70].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• For patients with SCD and proliferative retinopathy in cases of bilateral proliferative retinopathy, spontaneous hemorrhages, large dilated branches of new vessels, rapid neovascularization, and when one eye has already been severely affected by proliferative retinopathy, recommended is early treatment using the following methods — diathermy, cryotherapy, laser photocoagulation aimed at the regression of tissue neovascularization before the development of hemorrhage and retinal detachment. Therapeutic intervention is usually necessary [1, 2, 70].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

7.4 Cardiovascular Complications of SCD

Chronic heart failure in patients with SCD should be treated according to the relevant clinical guidelines. Severe anemia combined with chronic heart failure or angina pectoris requires compensation (regular transfusions of individually matched leukoreduced red blood cell suspension or therapy with #hydroxycarbamide** at an initial dose of 15 mg/kg/day (the dose is rounded to 500 mg) for adults, and an initial dose of 20 mg/kg/day for children under the control of leukocyte (neutrophil) and platelet counts) [66, 156]

• Antihypertensive therapy in patients with SCD is recommended in the following cases [1, 2, 28, 157]:

- when systolic BP increases by 20 mm Hg or diastolic BP by 10 mm Hg;

- when BP is above 130/85 mm Hg, if cardiac damage, nephropathy, or peripheral vascular disease is detected;

- when BP is 120/75 mm Hg in the case of proteinuria (more than 1 g/day).

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: ACE inhibitors or calcium channel blockers are particularly effective [1, 2, 28, 64–68]. Diuretics should be used with extreme caution, as they can provoke a vaso-occlusive crisis [1, 2, 28, 64–68]. Beta-blockers may be used [1, 2, 28]. Severe blood pressure elevation requires the exclusion of secondary hypertension.

7.5 Acute Chest Syndrome

Therapy with #hydroxycarbamide** reduces the incidence of acute chest syndrome (ACS) by 50% [1, 2, 28, 31, 32]. Regular transfusion therapy can also reduce the incidence of ACS [1, 2, 28, 31, 32].

• When ACS develops in patients with SCD, it is recommended to perform an acid-base balance and blood gas analysis, calculate the alveolar-arterial oxygen gradient and the PaO₂/FiO₂ ratio, and perform pulse oximetry to assess the severity of the patient's condition [1, 2, 31–35, 64–68, 158–160, 210].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: if the alveolar-arterial oxygen gradient worsens, the patient must be transferred to the intensive care unit to ensure adequate cardiorespiratory support.

• For patients with SCD and ACS with moderate hypoxemia (PaO₂=70–80 mm Hg, sO₂=92–95%), oxygen therapy at a rate of 2 L/min is recommended [32–35, 210].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

• Chest pain management and ergospirometry are recommended for all patients with SCD and ACS, as they can prevent hypoventilation in the majority of patients [1, 2, 31–35, 64–68, 158–160].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

• In the event of ACS, it is recommended to perform a red blood cell suspension transfusion (simple or exchange) [1, 2, 31–35, 64–68, 158–160, 210]. The main indication for transfusion in this case is low respiratory function; the goal is to prevent the progression of ACS to acute respiratory failure. Transfusion therapy is initiated at the first signs of hypoxemia (PaO₂ below 70 mm Hg breathing room air), or for patients with chronic hypoxemia, a decrease in PaO₂ by 10% or more from the baseline value.

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: Transfusion therapy is not indicated if a positive trend in the alveolar-arterial oxygen gradient is noted with adequate analgesia and incentive spirometry. Transfusion therapy should not be delayed, especially when the patient deteriorates. Altered thought processes in such patients are often mistakenly attributed to opioid excess, leading to delayed treatment of progressive ACS.

• Intravenous administration of systemic antibacterial drugs is strongly recommended in the presence of fever or severe ACS in patients with SCD, as it is quite difficult to exclude bacterial pneumonia or pulmonary infarction superinfection [1, 2, 31–35, 64–68, 158–160, 210]. It is recommended to use erythromycin in patients older than 14 years and drugs from the group of other beta-lactam antibacterial drugs (ATC code J01D ). The antibacterial therapy combination must always include a drug from the macrolide group (ATC code J01FA ) or fluoroquinolones (ATC code J01MA ), as atypical microorganisms are very frequently present.

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

7.6 Acute Hepatic Sequestration

Acute hepatic sequestration, a rarely diagnosed complication of vaso-occlusive crisis, is characterized by a rapidly progressive increase in liver size combined with a rapid decrease in hematocrit/Hb and an increase in reticulocyte count. Upon palpation, the liver is smooth, and its consistency varies. Total bilirubin can be significantly elevated with a predominance of the conjugated fraction, alkaline phosphatase activity elevated up to 650 IU/L (sometimes within normal limits), and hepatic aminotransferases are generally within normal limits or slightly elevated. Ultrasound and CT show diffuse hepatomegaly, and histological examination reveals markedly dilated sinusoids filled with sickle erythrocytes and erythrophagocytosis by Kupffer cells. Intrahepatic cholestasis may be present; hepatocyte necrosis is atypical. Recovery occurs quite frequently.

• In severe cases of acute hepatic sequestration in patients with SCD, recommended is an exchange transfusion of red blood cell suspension (simple transfusion carries a very high risk of a sharp increase in blood viscosity and total circulating blood volume upon resolution of the sequestration crisis); in moderately severe and mild cases, symptomatic therapy [1, 2, 38, 45, 161].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

7.7 Acute Splenic Sequestration

• In the event of acute splenic sequestration (ASS) in patients with SCD, recommended is the immediate initiation of treatment, which must be started without delay (ASS can be fatal within the first few hours), the main priority being the correction of hypovolemia via transfusion of individually matched leukoreduced red blood cell suspension [1, 2, 22, 47, 64–68, 133, 162–165, 210].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: following the transfusion of an individually matched leukoreduced red blood cell suspension, erythrocytes "trapped" by the spleen are released, along with which the size of the spleen decreases and Hb increases (often higher than expected considering the transfusion). ASS can recur, depending on the patient's further management: watchful waiting, chronic (regular) red blood cell transfusions, splenectomy (total) [1, 2, 22, 47, 64–68, 133, 162–166].

• Chronic (regular) transfusions of individually matched leukoreduced packed red blood cells are recommended for children with sickle cell disease (SCD) under 2 years of age [1, 2, 22, 47, 64–68, 162, 163].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

• All SCD patients older than 2 years who develop acute chest syndrome (ACS) are recommended to undergo splenectomy [1, 2, 22, 47, 64–68, 133, 162–166].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

7.8 Hematuria in SCD

• If hematuria develops in patients with SCD, after ruling out malignant renal disease [167], the following measures are recommended:

- bed rest,

- monitoring of diuresis (fluid intake/output),

- in case of significant blood loss – administration of iron supplements or packed red blood cell transfusions [1, 2, 168, 169],

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

7.9 Nocturnal Enuresis in SCD

• If nocturnal enuresis in SCD patients is not resolved by the age of 6 years, it is recommended to assess nocturnal hemoglobin oxygen saturation and recommend supplemental room oxygenation [1, 2, 170, 171].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

7.10 Management of Pregnancy and Childbirth in SCD

• SCD patients planning pregnancy, as well as parents of a child with SCD, are recommended genetic counseling to determine the risk of having a child with SCD or the probability of having another child with SCD in this family in subsequent pregnancies [213].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• When pregnancy occurs, female patients with SCD need early consultation with an obstetrician-gynecologist for a standard examination to minimize common risks of pregnancy complications. However, considering the presence of SCD, it is recommended to additionally perform the following examination [1, 2, 172]: quantitative assessment of hemoglobin types ratio, serum iron study, total iron-binding capacity study, serum ferritin study [172].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• In the case of uncomplicated pregnancy course in a patient with SCD, it is recommended to refrain from transfusion therapy. In the case of complications (preeclampsia, anemia with hemoglobin concentration below 90 g/L, increased frequency of pain episodes), as well as starting from week 20 in patients with multiple pregnancy or with a miscarriage or stillbirth in a previous pregnancy, it is recommended to start regular transfusions of individually matched leukodepleted red blood cell suspension. [173]

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: The requirement for packed red blood cells is thorough leukodepletion, with individual matching taking into account minor blood groups. If it is necessary to reduce the HbS content during pregnancy while Hb is high, it is necessary to first remove 500 mL of whole blood, then transfuse 2 units of packed red blood cells (mass). This can be done either manually or using a cell separator, while post-transfusion Hb should be 100–110 g/L and HbS 30–40% of the total Hb concentration [1, 2, 172–175].

Comments: Termination of pregnancy in SCD patients is possible up to 13 weeks of gestation, providing adequate pain relief [1, 2, 176]. At a gestation period of more than 13 weeks, pregnancy termination is associated with high risks for the woman.

Delivery in patients with SCD.

Cardiac function may be compromised by chronic hypoxia and anemia in the majority of patients.

• If a Cesarean section is necessary, it is recommended to perform a transfusion of individually matched leukoreduced packed red blood cells (simple or exchange) prior to surgery [1, 2, 172].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• In the postpartum period, replacement transfusion of individually matched leukodepleted red blood cell suspension is recommended for patients with SLE experiencing massive blood loss [1, 2, 172]. Frequently, the postpartum period in women with SLE is complicated by venous thromboembolism; for its prevention, early mobilization of the patients is also recommended [1, 2, 172].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Natalia S. Smetanina — MD, PhD, Professor, Member of the National Hematological Society, Member of the European Hematology Association, Member of the International BioIron Society; Deputy Director of the Institute of Hematology, Immunology and Cell Technologies, National Medical Research Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev of the Ministry of Health of the Russian Federation, Moscow

Elena A. Lukina — MD, PhD, Professor, Member of the National Hematological Society, Member of the European Hematology Association, Member of the International BioIron Society; Head of the Department of Hematology and Chemotherapy of Orphan Diseases, National Medical Research Center for Hematology of the Ministry of Health of the Russian Federation, Moscow

Elena A. Spiridonova — MD, PhD, Professor, Chief Researcher at the V.A. Negovsky Research Institute of General Reanimatology, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology of the Ministry of Health of the Russian Federation, Moscow; Member of the National Shock Society, Member of the Association of Pediatric Anesthesiologists and Intensivists of Russia

Nina V. Tsvetaeva — Candidate of Medical Sciences, Member of the National Hematological Society; Senior Researcher at the Sector for the Study of Non-Malignant Blood System Diseases, National Medical Research Center for Hematology of the Ministry of Health of the Russian Federation, Moscow

Rodion V. Ponomarev — Candidate of Medical Sciences, Head of the Sector for the Study of Non-Malignant Blood System Diseases, National Medical Research Center for Hematology of the Ministry of Health of the Russian Federation, Moscow

Lugovskaya Svetlana Alekseevna – Doctor of Medical Sciences, Member of the Russian Association of Medical Laboratory Diagnostics, Professor at the Department of Laboratory Diagnostics, Federal State Budgetary Educational Institution of Additional Professional Education "Russian Medical Academy of Continuous Professional Education" of the Russian Ministry of Health

Conflict of interest

Smetanina Nataliya Sergeevna – no conflict of interest

Lukina Elena Alekseevna – no conflict of interest

Spiridonova Elena Aleksandrovna – no conflict of interest

Tsvetaeva Nina Valentinovna – no conflict of interest

Ponomarev Rodion Viktorovich – no conflict of interest

Lugovskaya Svetlana Alekseevna – no conflict of interest

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Hematologist

2. Pediatrician

3. General Practitioner

4. General practitioner

5. Obstetrician-gynecologist

6. Surgeon

7. Otorhinolaryngologist

8. Ophthalmologist

9. Anesthesiologist-resuscitologist

10. Transfusiologist

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of reliable evidence (LRE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

No

Appendix B. Physician Action Algorithms

Appendix B1. Algorithm for diagnosis and treatment of SCD

Appendix B2. Algorithm for assessing the intensity and nature of pain in patients with SCD.

Appendix C. Patient Information

Sickle cell anemia is a genetically determined condition characterized by a change in the shape of red blood cells during oxygen delivery to tissues. As a result, the red blood cells change shape and can block small and sometimes medium-sized arteries, which is accompanied by severe pain in the area where blood flow is interrupted and by fever. At the same time, red blood cells break down, leading to a decrease in hemoglobin levels (anemia) and yellowing of the skin (jaundice). The initial manifestations of this disease can appear in the first months of life or at any other age. The earlier the disease manifests, the more severe its course. The only curative treatment for this condition is hematopoietic stem cell transplantation, which cannot be performed in all patients. In most cases, patients with sickle cell anemia receive medication to increase fetal hemoglobin levels in order to prevent severe manifestations of the disease. In severe cases, during surgical interventions, or when complications develop, packed red blood cell transfusions are administered to reduce the proportion of abnormal hemoglobin in the bloodstream. Due to the disease, the spleen may atrophy, leading to susceptibility to certain infections that can be fatal; therefore, it is very important to receive timely preventive vaccinations and take special systemic antibacterial drugs as prescribed by a doctor. It is important to regularly visit a pediatrician (general practitioner) and/or a hematologist who will monitor the treatment of your disease and help prevent the development of complications.

It is important to remember that patients with sickle cell disease need a high-calorie diet, adequate fluid intake (especially during hot weather and physical activity), and regular physical exercise (sports); hypothermia must be avoided as it can trigger a pain crisis.

When the first pain crisis occurs, be sure to consult your doctor on how to quickly and effectively relieve pain and in what cases to seek emergency care.

If your temperature rises, be sure to see a doctor immediately!

If you experience shortness of breath accompanied by a fever, or if the pain cannot be stopped within 2 hours, seek emergency medical care immediately.

Provided that all necessary treatment and follow-up examinations are carried out, the life expectancy and quality of life of patients correspond to population averages, and there are no significant restrictions in career choice.

Since the disease is genetically determined, DNA testing of the genes whose mutations lead to the development of this condition is required.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Pain Intensity Self-Assessment Scale for Children

Russian title: "Wong-Baker FACES Pain Rating Scale"

Original title (if applicable):

Source (official developer website, publication with

validation): Wong D. et al. Whaley and Wong’s Nursing Care of Infants and Children, ed. 6. St. Louis, Mosby, 1999. 1153 p. [177]

Type: rating scale

Purpose: pain assessment

Content, key (interpretation):

Appendix G2. Karnofsky Performance Scale

Russian title: Karnofsky Performance Scale.

Original title: Karnofsky Performance Status.

Original publication:

Karnofsky DA B.J.H. The clinical evaluation of chemotherapeutic agents in cancer. Evaluation of Chemotherapeutic Agents. // Columbia Univ. Press. 1949. P. 191–205.

Type: rating scale.

Purpose: to assess the patient's level of functioning in terms of their ability to care for themselves, daily activity, and physical capability (walking, working, etc.).

Content:

Note. The key (interpretation) is provided within the scale itself.