Continuing Education Activity

Sickle cell disease (SCD) is a group of inherited red blood cell disorders affecting about 1 in 500 African American children and 1 in 36,000 Hispanic American children. SCD leads to anemia and "sickle cell crisis" (SCC). The main clinical feature of sickle cell disease is the "acute painful crisis," which often requires hospitalization. SCC is primarily characterized by severe acute pain and impaired end-organ function. Symptoms of SCC depend on the areas involved. Pain can begin from any part of the body but frequently affects the extremities, back, and chest areas.

In a patient with SCC, evaluation is primarily performed to determine the severity of the acute disease flare. Treatment and management of SCD primarily consists of managing symptoms and associated complications. This activity for healthcare professionals aims to enhance learners' competence in selecting appropriate diagnostic tests, managing sickle cell disease and associated crises, and fostering effective interprofessional teamwork to improve outcomes.

Objectives:

• Apply knowledge of the pathophysiology of sickle cell crisis to patient assessment.

• Identify the complications of sickle cell disease.

• Implement evidence-based treatment and management options available for sickle cell crisis.

• Develop interprofessional team strategies for improving care coordination to manage sickle cell crises and improve outcomes.

Introduction

Sickle cell disease (SCD) is a group of inherited red blood cell disorders affecting about 1 in 500 African American children and 1 in 36,000 Hispanic American children.[1] SCD results in anemia and a "sickle cell crisis" (SCC). The main clinical feature of sickle cell disease is the "acute painful crisis," which often requires hospitalization.[2] The term "sickle cell crisis" is used to describe several acute conditions such as the vaso-occlusive crisis (acute painful crisis), aplastic crisis, splenic sequestration crisis, hyperhemolytic crisis, hepatic crisis, dactylitis, and acute chest syndrome. Other acute complications include pneumonia, meningitis, sepsis and osteomyelitis, stroke, avascular necrosis, priapism, and venous thromboembolism.[3] 

SCC is primarily characterized by severe acute pain and impaired end-organ function. Symptoms of SCC depend on the areas involved. For instance, a vaso-occlusive crisis, which most patients with SCD experience by the age of 6 years, can cause severe pain and swelling of both hands and feet (ie, dactylitis), primarily in young children. Pain can begin from any part of the body but frequently affects the extremities, back, and chest areas. SCD is diagnosed when laboratory evaluation identifies the presence of abnormal hemoglobin S (HbS). Genetic testing is also used to confirm the diagnosis. In a patient with SCC, evaluation is primarily performed to determine the severity of the acute disease flare. Treatment and management of SCD primarily consists of managing symptoms and associated complications.[4] 

About a third of sickle cell disease-related deaths occur within the home setting or 24 hours of hospitalization.[5]] Generally, adults are most likely to die from chronic complications, while children die acutely. The foremost causes of death in sickle cell disease are vaso-occlusive crises, cardiopulmonary threats, infections, and renal issues. Hypoxemia only compounds these problems.   

Etiology

Sickle cell disease is an autosomal recessive disorder of a gene mutation. On chromosome 11, nucleotide mutation leads to substituting glutamic acid to valine at position 6 on the β-globin subunit. This leads to changes in the physical properties of the globin chain. Many inciting factors lead to this physical property change of red blood cells, including hypoxia, dehydration, exposure to cold or weather changes, stress, and infections.[3]

Epidemiology

Sickle cell disease affects about 3 million people worldwide and approximately 100,000 people in the US.[6] The median life expectancy is 43 years. The prevalence of the disease is high among the people of sub-Saharan Africa, South Asia, the Middle East, and the Mediterranean. The most common genotype is homozygous hemoglobin SS (HbSS).[2] 

Pathophysiology

In the homozygous form of sickle cell disease, inciting triggers (eg, hypoxia, dehydration, exposure to cold or weather changes, stress) cause hemoglobin polymerization, resulting in the sickling and increased rigidity of erythrocytes.[2] The subsequent deoxygenation of erythrocytes, the sickling, and now damaged red blood cells attach to the endothelial wall, forming a mass comprised of leukocytes and platelets with adhesion molecules P and E selectins. The formation of these heterocellular aggregates physically causes small vessel occlusion and resultant local hypoxia. This process triggers a vicious cycle of increased HbS formation and releases inflammatory mediators and free radicals, contributing to reperfusion injury. Hemoglobin also binds to nitric oxide (NO), a potent vasodilator, and releases oxygen.

Other pathological events include increased neutrophil adhesiveness, nitric oxide binding, platelet activation, and hypercoagulability. Further microvascular occlusion occurs due to activated neutrophils. Inflammatory mediators (eg, plasma cytokines) lead to a proinflammatory state, causing further complications of vaso-occlusion. Experts postulate that the intestinal microbiome may be a potential trigger for the vaso-occlusive crisis.[7] While some triggers (eg, cold temperature, dehydration, low humidity, stress) for pain are identifiable, most episodes do not have an identifiable cause.[8] 

History and Physical

Vaso-Occlusive Crisis

Patients with vaso-occlusive crisis (VOC) present with moderate to severe pain, which has variable intensity and frequency. Young children can have severe pain and swelling of both hands and feet (ie, dactylitis). Most patients with SCD experience pain by the age of 6 years. Pain can begin from any part of the body but frequently affects the extremities, back, and chest areas. Fever can accompany vaso-occlusive crisis in some patients. Although pain in patients with SCD is likely to be due to VOC, performing a thorough evaluation for other life-threatening causes that can be misattributed to sickle cell pain is prudent.[9] There is no objective measure or lab test to determine the quality and severity of pain in SCD; therefore, a patient's self-report is the only available guide.

Splenic Sequestration Crisis

Patients with SCD have splenic infarction before the end of childhood, rarely after age 6. The spleen is affected due to its narrow vessels and its role as a key player in the lymphoreticular system. Acute splenic sequestration crisis is generally defined as acute splenic enlargement concurrent with a fall in the hemoglobin of more than 20% from the baseline in the face of a normal or increased reticulocyte count.[10] This happens when the spleen traps erythrocytes, leading to abdominal pain, distension, pallor, and tachycardia, followed by hypotension and lethargy. In severe cases, hypovolemic shock occurs with multiorgan failure, and death from cardiovascular collapse comes in a few hours.[11][12] Treatment involves the resolution of any infectious trigger, administration of intravenous (IV) fluids, and blood transfusion as needed, and, for those patients with repeated attacks, a splenectomy may need consideration. If not treated promptly, this can be a life-threatening situation.[9] Patients with sickle cell disease are usually hyposplenic (eg, functional asplenia) and should be considered immunocompromised.[13]  

Aplastic Crisis

Aplasia in sickle crisis presents with sudden pallor and weakness confirmed by rapidly dropping hemoglobin levels accompanied by reticulocytopenia. The usual trigger for aplastic crisis is parvovirus B19, which directly suppresses the bone marrow, affecting RBC production, but other viral infections can also cause it.[12] The shortened lifespan of RBC in SCD results in the worsening of the patient's baseline anemia, which can dip to dangerously low levels. There might be a slightly low platelet count and leukopenia. The infection is self-limited, typically lasting 7 to 10 days.[9] Aplastic crises can be handled with supportive care and simple transfusions.   

Acute Chest Syndrome

Acute chest syndrome (ACS) complication of SCD accounts for 25% of deaths and can follow vaso-occlusive crises. The trigger for ACS is frequently hypoxia due to hypoventilation of the chest caused by the vaso-occlusive crisis. It could also occur due to fat embolism originating from the distal bone in VOC. The hypoxia leads to the adhesion of sickled erythrocytes to pulmonary microvasculature, setting up local hypoxia in the lungs and causing the sickling of more RBCs; this sets up a vicious cycle. The presenting symptoms and signs include fever, cough, tachypnea, chest pain, hypoxia, wheezing, respiratory distress, and even failure. Any pulmonary infiltrates on chest radiography accompanied by abnormal lung findings should raise suspicion of ACS. Affected patients can rapidly progress to worsening respiratory failure and death if not aggressively treated and monitored.[14] 

Hemolytic Crisis

An acute drop in hemoglobin level marks this crisis. A hemolytic crisis is common in patients with coexistent G6PD deficiency.[9]  Another subset, another entity of this disorder, is known as Hyperhemolysis Syndrome.[15] This is a complication of repeated blood transfusions in sickle cell disease patients. Here, hemolysis occurs in both native and donor erythrocytes. Hyperhemolysis syndrome is found within many hemoglobinopathies, although its existence in sickle cell disease is foremost. Many theories have been forwarded to explain hyperhemolysis. One belief is that erythrocytes in sickle cell disease are damaged and stressed to the extent of increased surface phosphatidyl serine. This marks then for accelerated destruction by macrophages. This accounts for the increased LDH, increased bilirubin, decreased reticulocyte count, and an unchanged Hgb A / Hbg S ratio as both the donor and the native erythrocytes are destroyed. Contrast this with delayed hemolytic transfusion reactions where the ratio is decreased as only the donor cells are lysed. The treatment is to discontinue the blood transfusion and consider giving intravenous immunoglobulin with steroids in the future.   

Osteonecrosis 

Bone, as an organ, can undergo infarction in sickle cell disease, leading to osteonecrosis. Osteonecrosis affects upwards of 50% of sickle patients [16]. Plain X-rays, though helpful, aren't the gold standard, as is the MRI. The MRI is superior in sensitivity, specificity, and accuracy.[17] Osteonecrosis in sickle cell disease appears primarily in the long bones and secondarily in sites such as the cranial sections. Osteonecrosis can be found in other ailments, too, including steroid use, HIV, SLE, renal failure, multiple sclerosis, Sjogren syndrome, COVID, SARS (Severe Acute Respiratory Syndrome), leukemias, and lymphomas. The skeletal vaso-occlusive disease leads to inflammation with cytokine release, increased receptor activation of nuclear factor Kappa-Beta Ligand (RANK) signaling, and osteoclast activation.[18]  Osteonecrosis of the hip brings infirmity (as well as depression, anxiety, and a decreased quality of life - QOL) by causing subchondral bone collapse, leading to pain and disability.[19] Vitamin D deficiency also occurs in about a third of patients and compounds the situation. Protective factors for hip pathology were Hyrdrea use and high fetal hemoglobin. Some risk factors included an Hgb / Hct ratio more than 0.33 and the presence of BMP 6 (bone morphogenic protein) genotypes AT-rs267196 and AG-rs267201.[20] The latter is associated with chondroblasts and osteoblasts, valuable in bone formation. The treatment approach is multifaceted. Osteoblast (ABMDO) transplantation is being sought as a means to regenerate bone and promote healing.[21]  Intravenous bisphosphonates have been found to induce bone resorption as well as improve or resolve pain.[18] As Pyrophonate analogs, osteoclasts take up bisphosphonates, thereby causing their apoptosis. Interactions can occur in any non-long bone location, such as the vertebrae, which gives the endplate an H-shaped deformity, and in the cranium. Cranial bone infarctions may involve the mandibular bone and cause facial nerve palsy; orbital infarcts may result in subgaleal hematomas.[18][22][23] The MRI can display bone marrow edema and subperiosteal fluid. Bone infarcts can initiate a secondary effect of myositis on nearby muscles.[18] Creatine phosphokinase (CPK) becomes elevated and can be used as a marker for this finding. Parallel sequelae (eg, acute fasciitis, necrotizing myositis, and compartmental syndrome) can be seen.

Priapism

Priapism or unwanted penile erection occurs when there is vascular dysregulation of the exit tracts of the tunica albuginea, leading to penile engorgement.[24] A variety of known causes can lead to this finding, including spinal trauma, medications, and recreational substances. It affects 33% of adult males, with initiation in the prepubertal period and increasing with age. The symptoms include pain, mental stress (eg, depression and anxiety), and sexual dysfunction. Episodes lasting for more than 4 hours are a urologic emergency requiring either corporeal aspiration or shunt surgery.   

Nephropathy

Younger patients having sickle cell disease usually have an increased renal plasma flow and glomerular filtration.[25] However, this degrades to normal by adulthood and decreases further to suboptimal levels with increasing age. The mechanisms involved include oxidative stress and glomerular hypertension. Additional issues compound the problem, including medullary ischemia, endothelial damage, vaso-occlusive disease, and vascular conf=gestion. Albuminuria, which is the excretion of albumin more than 300 mg/day, is the earliest manifestation, leading to the slow progression to end-stage renal disease and failure. The presence of hematuria should suggest renal medullary carcinoma. ACE-1 or ARB therapy has decreased microalbuminuria, but neither has demonstrated the ability to improve kidney function.[6] Hydrea improves glomerular function and, like ACE medications, can improve albuminuria and slow its progression.[26] Hemodialysis carries a 1-year mortality of about 26% after dialysis has started.[6] Renal transplantation does become an eventual consideration. 

Cerebrovascular accident

In sickle cell disease, 11% of patients have had an overt stroke by the age of 20 years; 39% have had silent strokes by the age of 18 years.[6] The strokes may be complicated by cerebral vasculopathy, nocturnal hypoxemia, and Moyamoya, which is vascular arteritis of the brain blocked). An overt stroke involves the large arteries, including the middle and intracranial internal carotid arteries, while silent cerebral infarcts involve penetrating arteries. An overt stroke presents with physical or sensory deficits such as pain or seizures; silent strokes present with cognitive defects. Screening is performed using magnetic resonance angiography (MRA) over magnetic resonance imaging (MRI), as the former can evaluate cerebral vasculopathy. Acute strokes are treated with red cell exchanges, while chronic strokes can be dealt with using a transfusion schedule to keep the HbS below 30%. 

Girdle syndrome

Though rarely observed, the Girdle syndrome is a clinical syndrome in which vaso-occlusion occurs in the lungs, liver, and mesentery with a characteristic pain in a girdle-like distribution.[27][13] The diagnosis of vasa-occlusive crisis-related gastrointestinal ischemia is based on the presentation of acute abdominal pain crisis, a constellation of clinical findings, and a lack of alternate explanations for the situation. An abdominal-pelvic CT with contrast may reveal the target appearance of bowel wall thickening with mucosal hyperenhancement and submucosal edema. Other cases in the literature have shown mucosal necrosis, transmural necrosis, hemorrhagic changes with edema, and thromboses in the mesenteric arteries and arterioles. The rarity of ischemic bowel in sickle cell disease might be due to the extensive collateral circulation in the mesentery and bowel wall. The collateral circulation offers a modicum of protection. Supportive care brings resolution in uncomplicated cases.[27] In severe cases, there may be bowel perforation requiring emergency surgery.   

Evaluation

The diagnosis of SCD primarily involves laboratory studies that identify the presence of abnormal HbS with confirmation by genetic testing. [4] However, patients with sickle cell crisis should have routine laboratory examinations, including a complete blood count with differential, a reticulocyte count, a complete metabolic panel, and liver function tests, in addition to a comprehensive clinical evaluation. Imaging studies (eg, ultrasound, magnetic resonance imaging, Doppler) may be performed to evaluate for crisis complications. Type and screen blood for possible transfusion if needed. Inflammatory markers, including CRP, procalcitonin, and broad cultures, may be considered for fever and identification of the source of infection.

Clinicians should have a low threshold to obtain chest x-rays to facilitate early identification of ACS. An abdominal ultrasound may be considered for concerns of cholelithiasis. ABG can be obtained for hypoxemia and respiratory failure.[28] CT head and MRI brain would be indicated if there is suspicion of stroke.

Treatment / Management

Treatment and management of SCD primarily consists of managing symptoms and associated complications. Curative therapies such as stem cell transplant and gene editing are new, more complex, and costly. Unfortunately, nations rife with sickle cell disease may not have healthcare systems able to initiate these interventions.[29]

Vaso-Occlusive Crisis Management 

As a general rule, treatment requires an early diagnosis, prevention of complications, and management of end-organ damage.[6] Rapid pain assessment and initiation of analgesia should be undertaken promptly. Depending on the degree and severity of the pain, analgesic administration can be given intravenously (IV) or intranasally. Oral analgesics can be used for patients who are not in severe pain and can tolerate oral medications. Generally, the type, route, and dose of the analgesic should be individualized to the patient. Most guidelines recommend early initiation of parenteral opioid analgesics, usually with morphine at 0.1 mg/kg IV or subcutaneously (SC) every 20 minutes, and maintaining this analgesia with morphine at doses of 0.05 to 0.1 mg/ kg every 2 to 4 hours (SC/IV or orally). Those with persistent pain benefit from a PCA pump. Close monitoring of vital signs, including oxygen saturation, should be maintained with frequent pain severity or resolution reassessments.[28] If the pain is controlled, the patient may be ready for discharge with a home care plan and oral analgesia.[30] If the pain is uncontrolled despite the above treatment plan, consider hospitalization and the use of more potent forms of analgesia or higher doses titrated to the patient's needs. Simple or exchange transfusion may be warranted.[31]

Maintaining adequate hydration and being vigilant in identifying other causes of pain that may need additional treatment is prudent. Dehydration is one of the known factors of venous-occlusive disease, caused by the formation of deoxygenated HbS (deoxyHbs), which causes increased adherence and decreased flexibility of the erythrocytes. Plasma concentration is a function of the intracellular content of deoxy HbS. The sickling of erythrocytes depends on both factors. This is why patients who present with a painful crisis should be given fluids to slow down or stop the sickling process. Increasing the plasma volume decreases blood viscosity and indirectly reduces the amount and concentration of HbS within the red blood cells. 

For other entities like acute chest syndrome, splenic sequestration-supportive care with oxygen, judicious fluid administration, and transfusion therapy are needed. Close monitoring of oxygen saturation and respiratory status is also necessary, with particular attention to excessive sedation.[32] Empiric antibiotics, adequate analgesics, and simple or exchange transfusion may be considered for acute chest syndrome. Incentive spirometry, oral hydration, and comfort measures are recommended. Patients with splenic sequestration crisis resulting in hypovolemic shock, if not treated aggressively, have higher mortality. Management requires aggressive supportive care and blood transfusion.[28]  

Hydrea is an antimetabolite, a chemotherapy agent, that is foremost in treating sickle cell disease by augmenting HbF levels within the red blood cells. This mechanism decreases the rate of acute chest syndrome, pain, and other sequelae.[33] As a result, the quality of life is improved, hospitalizations are lessened, and transfusion needs are reduced.[34] Glutamine is required to synthesize amino acids that protect the erythrocyte against oxidative damage.[6] It does so by increasing the availability of Nicotinamide Adenine Dinucleotide (NAD), a redox factor.[5] NAD does not affect the Hgb, Hct, or reticulocyte count. Experts believe NAT reinstates the intestinal barrier, prohibiting bacterial entry.[35] These microbial interlopers are believed to compound the inflammation that promotes vaso-occlusive crises. Vaxelotor modifies HbS so that its polymerization is obstructed and its oxygen affinity increases.[6][5]  It improves hemolysis but has little effect on the sickle crisis. Vaxelotor effects with glutamine are synergistic; its effects with crizanlizumab are antagonistic. As an oxygen affinity modulator, vaxelotor reportedly has a relatively good safety profile and is used foremost in Europe.[36] Crizanlizumab is a humanized monoclonal antibody gG-2 Kappa that blocks P-selectin, the binding protein of sickle cells.[5][6] By doing so, crizanlizumab interrupts the vaso-occlusive process. It additionally blocks the adhesion of neutrophils and activated platelets.[36] Crizanlizumab is administered by monthly infusion.

Bone marrow transplant (BMT) has curative potential in sickle cell disease.[6] Hematologic stem cell transplant (HSCT) with HLA-matched sibling donors and either myeloablative or reduced-intensity conditioning regimens have a 5-year overall survival (OS) of about 90%. Matched unrelated transplants have difficulties with GVHD as high as 29%. Haploidentical HSCT, with posttransplant cyclophosphamide, has some utility. Umbilical cord transplant has shortcomings in terms of a low transplant cell dose and, if from an unmatched donor, the increased risk of graft rejection and GVHD. Gene therapy, with autologous transplantation, is developing into a possible modality for sickle cell treatment.[37] Functional human beta-globin genes (eg, Lentiglobin) are inserted ex-vivo into a patient's stem cells which are then transplanted back into the patient. These patients then produce HbA and have noteworthy reductions in hemolysis and vaso-occlusive crises. 

Long-term management of sickle cell disease is focused on the prevention of infection as well as the prevention of end-organ damage.[13] Besides lifelong administration of penicillin V, vaccinations against meningococcus, pneumococcus, and hemophilus influenza B are available to prevent infection with encapsulated organisms. COVID-19 and influenza vaccinations should be encouraged. Folate supplementation helps prevent a functional folate deficit.   

Differential Diagnosis

Vaso-occlusive crisis presents with severe pain with a relative lack of objective clinical signs. Differential diagnosis should include conditions specific to the site of the pain and not be blindly attributed to sickle cell disease. As an example, patients presenting with an abdominal painful crisis can mimic an acute abdomen, and the differential should include conditions that give acute abdominal pain, including acute appendicitis, acute pancreatitis, acute pyelonephritis, pelvic inflammatory disease, and hepatobiliary disease. Avascular necrosis and acute osteomyelitis are a consideration when there is persistent local bone pain.

Prognosis

Predictors of multiorgan failure in chest crises include thrombocytopenia, anemia, an increased respiratory rate, worsening hypoxia, multilobar chest x-ray involvement, and neurogenic compromise.[13] As infection can trigger a chest crisis, checking blood and sputum cultures if needed and nasopharyngeal aspirates for respiratory viruses is best.  

Complications

The adverse effects of therapy or its failure are a complication of the sickle patient; the damage is cumulative. The 3 most frequent complications of vaso-occlusive crises are infections, fever, and pulmonary problems.[38] The patient's activity, capacity, and reserve undergo a diminution with time. Neurogenic complications in sickle cell disease include silent cerebral ischemia, ischemic or hemorrhagic stroke, Moyamoya syndrome, posterior reversible encephalopathy syndrome, cerebral fat embolism, and cerebral venous sinus thrombosis.[39] 

Bacterial infections remain frequent and a severe complication of sickle cell disease.[40] Sickling leads to functional asplenia that leaves the patients at risk for life-threatening infections, especially from encapsulated microbes such as Streptococcus pneumoniae, Neisseria meningitides, and Haemophilus influenza type b. Some world areas incur additional infectious hazards like hepatitis B, salmonella, and malaria.[41] Tragically, poverty and the lack of health care support only magnify these problems. 

Treatment is known, but there is a lack of presence. Acute chest syndrome is the leading cause of death in sickle adults. Infectious causes predominate here, including mycoplasma pneumonia and respiratory syncytial virus (RSV), which are common in children; chlamydia is common in adults. Stroke is the leading cause of disability in sickle cell patients.[40] Ischemic stroke occurs primarily in children, whereas cerebral hemorrhage occurs primarily in adults of the ages of 30s to 40s. Once an acute stroke develops, an exchange transfusion protocol should be started without delay. After a stroke, there is a high probability of recurrence unless these transfusion protocols are initiated. Transfusions are indicated in acute chest syndrome, stroke, aplasia, and sequestration problems. However, the risks include alloimmunization, delayed hemolytic transfusion reaction, hyperviscosity, and iron overload.   

Consultations

Consultation with a hematologist is helpful. 

Deterrence and Patient Education

Patient medical education can prevent the need for more aggressive intervention later because the patient can monitor their condition and report crisis symptoms as they initially develop. While patients may not be medically trained, they and their caretakers can be taught what to observe and how to react. Sickle cell crises can cause cumulative damage. The sooner they can be settled, the better the long-term quality of life for the patient.

Pearls and Other Issues

Early detection and rapid initiation of appropriate treatment for several acute conditions, including vaso-occlusive, aplastic, sequestration, and hemolytic crises, is needed. These crises, if not treated early, can result in mortality.

Enhancing Healthcare Team Outcomes

SCD is a hereditary hemoglobinopathy characterized by abnormal, crescent-shaped red blood cells, leading to vaso-occlusive crises, anemia, and organ damage. Clinicians must recognize the diverse clinical manifestations, including pain crises, acute chest syndrome, and stroke. Comprehensive care involves hydroxyurea for symptom management, transfusions for complications, and potentially curative stem cell transplantation. Regular monitoring, vaccination, and patient education are crucial for preventing and managing complications. An interdisciplinary approach, considering both acute crises and long-term complications, is vital for optimizing outcomes in individuals with SCD.

Patients with sickle cell crises are best managed by an interprofessional team that includes specialist and primary care physicians, nurses, pharmacists, physical therapists, radiology and laboratory technicians, and genetic counselors. The key is rapid hydration and pain control. In addition, oxygenation should be monitored. Finding and treating the trigger of the crisis is critical to prevent a recurrent crisis. Despite optimal treatment, the quality of life of most patients with sickle cell is poor, marked by repeated admissions. The pharmacist should ensure that the patient complies with hydroxyurea because it has been shown to reduce the adverse effects of the disease.