Essentials of Hematology

Pathophysiology

Hemoglobin A is composed of two α- and two β-globin chains. Hemoglobin S results from a single base-pair mutation in the β-globin gene on chromosome 11, which results in the replacement of a negatively charged, hydrophilic glutamate residue with a noncharged, hydrophobic valine residue. This hydrophobic valine is exposed when HbS is deoxygenated and is stabilized by binding the same hydrophobic valine pocket on other HbS molecules, thereby leading to polymerization of HbS, precipitation and hemolysis.

In contrast to prior simplistic models in which sickled cells were simply thought to block flow through the microcirculation, the pathophysiology of sickle cell disease is now understood to be considerably more complex. This understanding is, in turn, leading to more therapeutic interventions. Any factor that promotes hemoglobin crystallization (e.g., hypoxia, acidosis, and cellular dehydration) or prolongs capillary transit time (e.g., dehydration, hypothermia, leukocytosis, thrombosis, and inflammation) increases HbS polymerization and formation of sickled cells. Inflammation, vascular endothelial adhesion abnormalities, platelets, and coagulation cascade activation all contribute to vasoocclusive episodes. The sickle red cell membrane becomes compromised by exposure to destructive oxidizing effects of precipitated HbS, thereby leading to altered permeability to sodium, potassium, and calcium, causing dehydration of the cell and irreversible sickling. Membrane abnormalities of phospholipid content also contribute to its deformability, and exposure of phosphatidyl serine facilitates activation of the clotting cascade. These and other factors lead to entrapment of irreversibly sickled red cells in the microcirculation, activation of coagulation and inflammatory pathways, ischemia, and infarction of tissue. At the same time, chronic intravascular hemolysis decreases production of NO, while increased scavenging decreases the bioavailability of NO. The resulting NO deficiency causes endothelial dysfunction and disease complications, such as pulmonary hypertension, priapism, and skin ulceration.

Clinical and Laboratory Features and Treatment

Sickle cell disease is a multisystem process involving most organs of the body and at times necessitating surgical intervention. While there is considerable variation in disease severity, all patients have a progressive clinical course. Therapeutic interventions and genetic factors account in large part for the differences in outcome. Children with persistence of hemoglobin F (which itself protects against the effects of deoxygenation on red cells) and those with HbSC or HbSβ ⁺ have fewer complications than those with HbSS or HbSβ ⁰ .

Early diagnosis and treatment of sickle cell disease have been facilitated by the widespread use of universal neonatal screening, which was first used in the state of New York in 1975. Most screening programs for sickle cell disease use isoelectric focusing of an eluate from dried blood spot samples, a technique that is also used to screen for other disorders. A few programs use high-performance liquid chromatography. Because a small percentage of children with sickle cell disease are not African American (i.e., Native American, Hispanic, and Caucasian), selective screening may not detect all affected infants. As of 2006, all 50 states and the District of Columbia screen neonates for sickle hemoglobinopathies. Families of infants diagnosed with sickle trait (HbAS) on neonatal screening may not be made aware of the diagnosis, but reports of perioperative complications suggested to be associated with sickle cell trait are exceedingly rare. Affected children born within the United States before universal neonatal screening and those born outside the United States without routine health care may not have received diagnosis and appropriate care before surgery. Notwithstanding the controversy over the utility of nonselective preoperative screening, children at risk whose hemoglobin status is unknown preoperatively should have a sickle-screening test, followed by a hemoglobin electrophoretic evaluation if screening is positive. However, infants younger than 6 months of age may have a false-negative screening test result because of the presence of fetal hemoglobin, although electrophoresis is diagnostic at all ages. Children older than 10 years of age with a normal hemoglobin value, standard peripheral blood smear, and unremarkable clinical history are at low risk of having a clinically significant hemoglobinopathy.

Common clinical symptoms of sickle cell disease in children include chronic hemolytic anemia, pain crises secondary to recurrent vasoocclusive episodes, acute chest syndrome (ACS), infection, renal insufficiency, osteonecrosis, and cholelithiasis. Pulmonary hypertension, priapism, and skin ulcerations may also occur and are related to the degree of red cell hemolysis. Chronic pulmonary and neurologic disease (e.g., stroke) are additional causes of significant morbidity and mortality. In the perioperative period, the most common complications in sickle cell children include ACS (about 10%), fever or infection (about 7%), vasoocclusive episodes (about 5%), and transfusion-related events (about 10%).

Chronic hemolytic anemia is a hallmark of HbSS disease. It is characterized by a baseline hemoglobin value of 5 to 9 g/dL (often more than 9 g/dL in HbSC disease), reticulocytosis (5% to 10%), and a distinctive red cell morphology observed on a peripheral blood smear. Red cell fragility and chronic hemolysis are associated with anemia, increased red cell turnover, and a propensity to form biliary stones. The anemia may be complicated by other events, such as acute splenic sequestration, typically occurring in infants and young children after a viral illness; or an acute cessation of red cell production, the equivalent of transient erythroblastopenia of childhood and typically associated with parvovirus B19 infection. For some children, chronic and acute severe anemia are managed with RBC transfusions, although these children are prone to develop alloantibodies to RBC antigens, and untreated iron overload resulting from recurrent transfusions can lead to life-threatening cirrhosis and cardiac failure. Most children are maintained on chronic folic acid therapy to prevent megaloblastic erythropoiesis that can result if increased demands for purine synthesis from red cell production are not met.

Vasoocclusive episodes in sickle cell disease occur as a result of episodic microvasculature occlusions at one or more sites. The occlusive process occurs most commonly in the phalanges (i.e., dactylitis or hand-foot syndrome), long bones, ribs, sternum, spine, and the pelvis; it also can occur in the mesenteric microvasculature, producing abdominal pain that may mimic a surgical acute abdomen. Pain associated with vasoocclusive episodes should be managed with a multidimensional approach including reversal of potential triggers (via warming, hydration, and ambulation), distraction, psychological and behavioral interventions, and complementary modalities in addition to analgesic medications. Initial pharmacologic management often entails scheduled antiinflammatory agents because inflammation is central to the vasoocclusive process, and these agents synergize with opioids to provide analgesia. It is essential to foster an ideal environment for pain control (e.g., calm, pleasant distractions, supportive personnel and objects). Hydroxyurea is used to prevent vasoocclusive episodes and end-organ damage, and it is now widely recommended for all patients with HbSS and HbSβ ⁰ . Although grossly underused, hydroxyurea is a safe and effective component of chronic management in decreasing the frequency of events through several mechanisms; inhibiting hemoglobin precipitation by increasing fetal hemoglobin concentrations; reducing white blood cell count; modifying the inflammatory response; and facilitating NO metabolism. Inhaled NO or precursors of NO may prove to be effective therapy for vasoocclusive episodes.

ACS is characterized by acute respiratory symptoms concurrent with new infiltrate(s) observed on chest radiograph. ACS frequently occurs 2 to 3 days after a vasoocclusive episode, and although its clinical presentation varies, it often includes any, or all, of the following: fever, tachypnea, cough, and hypoxemia. The process may be self-limited over a period of a few days, or it may progress to respiratory failure (15%) and even death. The inconsistent presentation in part reflects the complex and variable pathogenesis of ACS. An episode may have a single or multiple causes, including infection (i.e., bacteria or atypical bacteria [often Chlamydia or Mycoplasma ], viruses, or a combination of agents), pulmonary fat embolism, pulmonary infarction, and pulmonary hemorrhage. Acute management includes supportive care and oxygen, antibiotics that treat encapsulated and atypical organisms, bronchodilators, pain control, ventilatory support as needed, and transfusion. Incentive spirometry or continuous positive airway pressure can be helpful, especially in the perioperative setting. Hydroxyurea therapy and chronic transfusion therapy decrease the frequency of ACS, whereas inhaled NO, NO precursors, and antioxidants (e.g., arginine and glutamine) may attenuate the process acutely. Airway reactivity is also common in children with sickle cell disease, in part due to NO deficiency, and it is responsive to bronchodilator therapy. In later life, children with sickle cell disease may develop restrictive lung disease and pulmonary hypertension as a result of repeated ACS-induced lung injury and chronic inflammation. NO deficiency, the result of decreased production, increased consumption, or altered metabolism, may also play an important role in these processes.

Infections are common because of deficits in the immune system and the specific effects of splenic atrophy and dysfunction that occur over the first few years of life. As a result of susceptibility to overwhelming infection by S. pneumoniae and H. influenzae type B, young children receive penicillin prophylaxis until 6 years of age and bacteria-specific immunizations in addition to those routinely administered to children. A host of infectious organisms have been implicated in ACS, and infection with gram-negative organisms (e.g., osteomyelitis caused by Salmonella ) is common in older children and adults.

Stroke is a potentially devastating complication that occurs in about 10% of children; as high as 40% have silent infarcts and 10% have overt strokes. One-fourth of children have motor or cognitive deficits at the time of presentation for surgery. A child's first stroke often appears as early as 2 to 5 years of age. Risk factors include reduced hemoglobin concentration, increased concentration of HbS, increased leukocyte count, and a history of dactylitis. Pain episodes, ACS, and infection may precipitate strokes. Children suffering an acute stroke are managed supportively with emergent exchange transfusion to reduce the concentration of HbS to less than 30%, followed by chronic transfusions and hydroxyurea administration to minimize the risk of recurrence. The thrust of the current management of stroke is prevention. Yearly screening with transcranial Doppler starting at age 2 identifies most children at high risk, and subsequent management with chronic transfusion and hydroxyurea therapy may minimize the risk of a future stroke.

Renal abnormalities can include proteinuria, hematuria, hyposthenuria, and renal tubular acidosis. Acute and chronic renal failure may develop, and angiotensin-converting enzyme (ACE) inhibitors may be of benefit of resulting hypertension. Renal dialysis and transplantation have proven successful interventions for renal complications of the disease.

HbAS is usually benign, although it may be characterized by microhematuria and hyposthenuria, and sickling may occur under extremely altered physiologic circumstances (e.g., cardiopulmonary bypass). There is also a small but significant risk of pulmonary embolism. An increased risk of rhabdomyolysis with exercise, as well as sudden death with extreme exertion in individuals with HbAS, has led to the controversial mandate to offer trait testing to all National Collegiate Athletic Association (NCAA) Division I athletes.

Children with HbSC disease usually have a greater baseline hemoglobin concentration and fewer complications than those with HbSS disease. Because splenic function is often preserved, the risk for infection in early childhood is reduced. Children with HbSC disease are more likely to have proliferative retinopathy and avascular necrosis of long bones.

Children with HbSβ ⁰ (i.e., one sickle globin allele and one thalassemic allele expressing no β-globin) have a course identical to that of HbSS, whereas those with HbSβ ⁺ (i.e., one sickle globin allele and one thalassemic allele expressing β-globin at a reduced level) tend to have a more benign course that is proportional to the amount of normal β-globin expression. The coexistence of hemoglobin S with α-thalassemia produces a variable clinical picture, but it may predispose children to a significant incidence of pain episodes.

Many additional approaches to sickle cell care are being investigated and are notable for targeting multiple aspects of the complex physiology. These include administration of short-chain fatty acids such as butyrate or demethylating agents such as decitabine to induce production of hemoglobin F; small molecules to interfere with polymerization; antibodies to alter cell adherence; ion channel inhibitors to decrease cellular dehydration; NO-related compounds and precursors; and manipulation of inflammatory pathways. New therapeutic targets such a BCL11A, a zinc finger protein that plays a key role in the silencing of fetal globin genes, is being targeted by multiple mechanisms. HSCT is increasingly used as a curative intervention for sickle cell disease. While cure rates with HLA-matched sibling donors exceed 80%, the lack of such donors for most patients has led to the increasing use of cord blood units as well as unrelated and haplo-identical donors. To circumvent many complications of transplantation, gene therapy protocols using a child's own modified stem cells are underway, and multiple gene editing approaches are being pursued.

Perioperative Considerations

Perioperative morbidity and mortality are greater in children with sickle cell disease than in the general population. These children often require surgical procedures. The most common include cholecystectomy ; ear, nose, and throat procedures ; and orthopedic procedures (especially hip procedures for osteonecrosis). Placement of long-term vascular access for transfusions, antibiotics, analgesia, and other therapies is frequently performed. The Cooperative Study of Sickle Cell Disease reported that 7% of all deaths among children with this disease were related to surgery. Early reviews reported perioperative mortality rates as great as 10% and morbidity rates as great as 50% for children with sickle cell disease. Studies published in the 1990s indicated that the 30-day mortality rate was about 1%. In a group of more than 600 patients managed according to standard guidelines of care and prospectively studied, the incidence of any complication was about 30%, and the incidences of ACS and vasoocclusive pain episodes were 10% and 5%, respectively. Patient factors (e.g., age, history of pulmonary disease, number of prior hospitalizations) and surgical factors (i.e., invasive vs. superficial) appear to affect the incidence of complications. The impact of newer interventions and technologies (e.g., laparoscopic and robotically assisted cholecystectomy and splenectomy) on perioperative morbidity and mortality rates is unclear, although more recent reports cite reduced rates of complications than in the past. Although multiple anesthesia and surgical approaches are under investigation, there is a dearth of comparative studies identifying optimal perioperative care for these children.

The principles of optimal perioperative care are based on maintaining optimal physiologic parameters throughout the perioperative period, avoiding factors that may precipitate a sickle crisis, optimizing pain management, and close consultation among hematologists, surgeons, and anesthesiologists ( Table 10.9 ). The child with sickle cell disease who is undergoing surgery should be viewed and managed primarily as a hematology patient whose care is being shared with, rather than assumed by, the surgeon and anesthesiologist during the perioperative period. Avoiding unnecessary and potentially dangerous surgical procedures (e.g., exploratory laparotomy to rule out appendicitis in a child who is experiencing an abdominal pain crisis) and minimizing perioperative complications should be the focus of the multidisciplinary care team. Based on a survey of perioperative management of sickle cell disease among anesthesiologists in North America, most anesthesiologists consult with hematologists in all cases or on a case-by-case basis.

Although there is no evidence to support or refute many of the long-standing guidelines for perioperative care and individual practices vary widely, it seems prudent to avoid those factors that may promote intravascular sickling: hypoxia, acidosis, hyperthermia, hypothermia, and dehydration. Meticulous attention to pain management is also essential because perioperative vasoocclusive pain is common and is associated with ACS. Monitoring vital signs throughout the perioperative period is mandatory, especially monitoring oxygenation with pulse oximetry. Oxygen saturation as determined by pulse oximetry may underestimate measured oxygen saturation in patients with sickle cell disease, although this is usually clinically insignificant. Because ACS, a common (10%) and potentially life-threatening complication of surgery, occurs 1 to 3 days postoperatively, it is important to extend adherence to guidelines of care into the postoperative period, regardless of the apparent well-being of the child. In light of the renal-concentrating defect found in these patients, perioperative hydration is important to maintain and may require in-hospital preoperative care, although one must be aware that overhydration may compromise vulnerable cardiovascular and respiratory physiology.

Transfusion in the perioperative period remains a controversial subject despite several studies suggesting its benefit. Transfusion of non-HbS RBCs to a child with sickle cell disease has several beneficial effects: correction of anemia; dilution of HbS red cells; compensation for blood loss; and prevention of some complications (e.g., stroke). However, transfusion is not without risks, including alloimmunization, transfusion reactions (about 7% in the perioperative period), infection, iron overload, time, and expense. Although there have been many reports of surgery performed safely in children with sickle cell disease without preoperative transfusion, uncontrolled studies indicate that preoperative transfusion does decrease the rate of perioperative complications. The Preoperative Transfusion in Sickle Cell Disease Study Group demonstrated prospectively in 604 operations (70% were cholecystectomies and otolaryngologic and orthopedic operations) that simple transfusion (i.e., correction of preoperative anemia to 10 g/dL with simple transfusion) was as effective as aggressive transfusion (i.e., lowering the preoperative HbS level to <30%, often with exchange transfusion) in preventing perioperative complications and was associated with less alloimmunization and fewer transfusion-related complications in children.

To directly determine if transfusion prevents perioperative complications in the current era of surgical and anesthesia practices, an international randomized trial was initiated, the Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) trial. However, this trial was halted early during the recruitment process as a result of an excessive number of complications in the nontransfusion group. This led to the continued recommendation of transfusion for moderate and complicated operations in sickle cell patients. It is currently recommended that most children with HbSS undergoing most surgical procedures receive preoperative correction of anemia with a “simple” (i.e., direct) transfusion targeting a hemoglobin concentration of 10 g/dL. Children maintained on chronic transfusion programs (e.g., for stroke prevention or acute chest) should continue such management preoperatively, and common sense dictates performing surgery soon after a scheduled transfusion. Children with sickle cell disease who are undergoing magnetic resonance imaging (MRI) and other examinations under sedation/anesthesia without prior transfusion do not have increased complications. Recommendations for children with HbSC disease are less clear because these children typically maintain a baseline hemoglobin concentration at about 10 g/dL. For HbSC children who have a history of ACS, frequent pain crises, underlying pulmonary disease, or other complications, it is recommended that they receive selective preoperative exchange transfusion to reduce the HbS concentration without increasing total hemoglobin. Because of the high risk of alloimmunization in the sickle cell population, blood for these patients should undergo the following preparation: extended phenotype matching, including Rh, Cc, D, Ee, and Kell in addition to ABO ; leukocyte reduction; and screening for sickle cell hemoglobin. Directed donation of blood from family members should be avoided if the child is an HSCT because it can lead to alloimmunization and later graft rejection.

Anesthetic agents and techniques do not have a clear effect on perioperative outcomes for children with sickle cell disease. Inhalational anesthetics do not affect the sickling process, although there is experimental evidence suggesting that halothane may increase the viscosity of sickled blood. Pharmacokinetics of some agents commonly used with general anesthesia such as atracurium may be altered in this population. Regional anesthesia has been associated with an increased risk of postoperative complications in one retrospective study, but it has not been shown to affect perioperative outcome in others. The vasodilatory and analgesic properties of regional anesthesia can be effective in the management of vasoocclusive episodes and priapism and in providing perioperative anesthetic care.

Other aspects of anesthetic care of sickle cell disease patients merit consideration. Hyperventilation should be avoided because of its potential to reduce cerebral perfusion in children at an increased risk for stroke. The use of a tourniquet in HbSS and HbAS diseases has been questioned. However, tourniquets have been applied intraoperatively for up to 2 hours without complication, and the predominance of evidence supports their safe use as long as they are used carefully and selectively in combination with general guidelines of perioperative care. Intraoperative blood salvage with cell saver devices has been used safely in sickle cell patients, although there is some evidence that the salvage device itself may produce sickling in the processed blood, even sickle trait blood. Cardiopulmonary bypass seems to present conditions that are favorable toward sickling, given the cold, hypoxic, acidotic, and stagnant environment created. Although there are reports of bypass surgery conducted in children with HbSS or HbAS with standard bypass procedures without transfusion, these children usually are managed with aggressive exchange transfusion before or during bypass.

While comparative studies that specifically address optimal postoperative care, understanding of the pathophysiology of the disease and studies of sickle cell pain suggest that postoperative care should minimize postoperative pain to allow deep inspirations, use of incentive spirometry, and encouraging early ambulation to prevent ACS. Maintaining euvolemia, normal body temperature, and sufficient oxygenation should minimize the risk of vasoocclusive pain at this time of increased risk due to anesthesia and postoperative inflammation.

Pathophysiology

Anemia in thalassemia is the result of hemolysis and ineffective erythropoiesis; the latter results, in turn, from accelerated cell apoptosis triggered in part by excess deposition of unpaired globin chains in erythroid precursors. Unpaired globin subunits are oxidized and form hemichromes, whose degree of formation affects the degree of hemolysis. Precipitation of hemichromes leads to a complex process that includes release of toxic agents and formation of reactive oxygen species; alteration of red cell membranes causes cells to become aggregates that lead to embolic complications and activation of the coagulation process. As a result of chronic anemia and ineffective erythropoiesis, bone marrow expansion and extramedullary hematopoiesis may develop in the liver and spleen. Marrow space expansion may occur at sites such as the cranium and paravertebral areas, thereby causing pathologic fractures, disfiguring bony changes, and pain. Erythroid hyperplasia and ineffective erythropoiesis lead to inappropriately low hepcidin expression (a polypeptide that inhibits iron absorption by binding to the ferroportin in the gut wall and macrophages), resulting in increased iron absorption from the gastrointestinal tract and iron overload, even in the absence of transfusion iron overload. Iron overload and deposition lead to fibrosis and cirrhosis with concomitant organ dysfunction and eventual failure. While there are many target organs for iron overload, the most relevant are liver, pancreas, heart, and pituitary; the extent of iron deposition in each can be accurately and sequentially monitored by MRI.

Clinical and Laboratory Features and Treatment

Disease severity in α-thalassemia typically reflects the complete loss of expression of between one and all four of the α-globin genes. A four-gene globin deletion typically results in hydrops fetalis with in utero or perinatal death unless diagnosed early and supported with in utero transfusions. A three-gene deletion, or hemoglobin H (HbH) disease, is relatively benign, characterized by chronic hemolytic anemia, which may be exacerbated by exposure to stress and oxidants. The few patients with profound anemia or requiring intermittent transfusion therapy often have a two-gene deletion along with a hemoglobin Constant Spring (HbCS) mutation (HbH-Constant Spring). A two-gene deletion alone is benign, manifest by a mild, clinically insignificant microcytic anemia. A one-gene deletion results in a silent carrier state with no anemia or microcytosis.

In contrast to α-thalassemia, β-thalassemia reflects partial or complete loss of expression of the β-globin genes. The broad spectrum of disease results from the number of genes affected and the degree to which each gene is affected. When only one β-globin gene is affected (i.e., β-thalassemia trait), mild microcytic anemia is the primary clinical manifestation. When both β-globin genes are affected, the clinical picture may be mild to moderate, potentially requiring intermittent, but not chronic transfusions (thalassemia intermedia), or severe, requiring chronic transfusions (thalassemia major or Cooley's anemia). Children with hemoglobin E (HbE)/β-thalassemia manifest a dramatic range of severity ranging from very mild to severe and transfusion-dependent.

The clinical problems in thalassemia are those associated with chronic anemia, the physiologic response to ineffective erythropoiesis, iron overload from transfusions and paradoxical increased iron absorption, as well as chelation therapy. Clinical problems include transfusion-associated alloimmunization and infection, splenomegaly, bone abnormalities (due to extramedullary hematopoiesis, chelation therapy, and other factors), endocrine dysfunction (including hypogonadism, hypopituitarism, and diabetes mellitus), short stature, pulmonary hypertension, venous thrombosis and thromboembolism, and cardiomyopathy (primarily due to iron overload). Thalassemia patients also may be hypercoagulable, a condition that may be exaggerated after splenectomy.

The approach to moderate to severe disease is to balance transfusion to treat the underlying anemia and suppress erythropoiesis while minimizing and aggressively treating iron overload. Phenotypic matching and leukocyte reduction of transfused blood can reduce immune complications, and careful surveillance for end-organ damage and endocrine management is essential. When an appropriate donor is available, HSCT is recommended before severe liver damage occurs because it provides a potential cure for thalassemia. To ameliorate the course of the disease, other therapies are being investigated, including administration of erythropoietin, fetal hemoglobin modifiers (e.g., hydroxyurea, butyrate), and antioxidants. Of particular excitement is the modulation of ineffective erythropoiesis by manipulating erythropoietin gene signaling via inhibition of the JAK2-STAT5 pathway. Increasing numbers of gene therapy trials are currently underway and proving successful, and gene editing approaches similar to those with sickle cell disease are being pursued.

Perioperative Considerations

Children with moderate or severe thalassemia may require cholecystectomy and vascular access placement for frequent transfusions. While splenectomy can aid transfusion support, it is avoided if possible (particularly for thalassemia intermedia) because of the increased risk of embolic disease after splenectomy. If splenectomy is performed, short-term antithrombotic prophylaxis with unfractionated or low-molecular-weight heparin should be considered during and after surgery. Pneumococcal vaccination protocols, as well as prophylactic antibiotic protocols for asplenic patients, should be followed. Patients with thalassemia who have undergone splenectomy should be considered at high risk for thrombosis and should be administered appropriate prophylaxis therapy when exposed to transient thrombotic risk factors such as surgery, pregnancy, and immobilization Demineralized long bones may be prone to fracture, and older children may require osteotomies for bony deformities.

Perioperative management for thalassemia has not been extensively studied. It is important to consult with a hematologist to define transfusion parameters and the optimal preoperative hemoglobin level. In addition, one should be aware of the risk of the possible complications of iron overload in these patients: liver dysfunction; diabetes; pituitary dysfunction; and cardiac dysfunction (the latter an indication for preoperative electrocardiogram and echocardiogram). Bony abnormalities of the maxillofacial area may render securing the airway challenging. Similarly, extramedullary erythropoiesis can lead to paravertebral masses potentially interfering with epidural or other nerve blocks. Laparoscopic and robotic techniques for cholecystectomy and splenectomy have been used successively in children with thalassemia, although perioperative hypertension may be a common problem in laparoscopic splenectomy. Perioperative considerations and concerns for children with thalassemia, especially for those with thalassemia major, are listed in Table 10.10 .