Factor-Replacement Therapy

Factor-replacement dosing is based on the type of product and individual pharmacokinetics. The plasma half-life of unmodified and plasma derived factor VIII is approximately 12 hours, and the plasma half-life for unmodified and plasma derived factor IX is approximately 24 hours. The prolonged factor VIII products have an estimated extended half-life of approximately 18 hours and the prolonged factor IX products have an extended half-life of 85 to 90 hours. Peak plasma factor concentration is reached 30 minutes to 1 hour after an intravenous infusion. Table 7.1 provides formulas for factor correction.

In the United States, the majority of children with severe hemophilia are treated with prophylactic therapy, which consists of either IV factor administration at regular intervals to prevent spontaneous bleeding or subcutaneous injections of emicizumab (see Table 7.1 ). Patients with mild or moderate hemophilia are treated as needed to prevent bleeding before surgical procedures. For nonlife-threatening bleeding episodes, such as hemarthroses, coagulation factor activity should be raised to 40% to 50% of normal. For life-threatening bleeding, coagulation factor activity is raised to 80% to 100% of normal.

The goal of treatment in a patient with hemophilia undergoing a surgical procedure is to obtain a factor level of 0.8 to 1.0 units/mL (80%–100%) before the procedure. Factor replacement is continued into the postoperative period to prevent excessive bleeding and promote adequate healing. Factor replacement is usually continued for 2 to 3 days after a minor procedure and 10 to 14 days after major procedures. Intermittent dosing or continuous infusion factor replacement can be used to accomplish this goal. Preoperative evaluation for elective procedures in a patient with hemophilia should include measurement of an inhibitor titer and assessment of factor recovery and half-life.

Adjuvant hemostatic therapies include antifibrinolytics, such as aminocaproic acid and tranexamic acid, that inhibit clot lysis. Antifibrinolytic agents are particularly beneficial for surgeries that involve the oral mucosa (i.e., adenotonsillar procedures or dental extractions) because of a high concentration of fibrinolytic enzymes in saliva. Aminocaproic acid can be administered orally or IV, 100 mg/kg (maximum 6 grams) every 6 hours. Tranexamic acid is administered IV 10 mg/kg every 6 to 8 hours. A range of dosing has been reported for oral tranexamic from 10 to 25 mg/kg orally every 6 to 8 hours (maximum of 3900–6000 mg/day) has been reported.

An alternative hemostatic option for some patients with mild hemophilia A is desmopressin acetate (DDAVP). DDAVP is a synthetic vasopressin analog that causes release of factor VIII and von Willebrand factor from endothelial cells. In patients with mild hemophilia A, there is a significant variation in individual response to DDAVP, and it should not be used in severe or moderate hemophilia A. A trial administration to demonstrate an adequate rise in factor VIII levels is recommended before using DDAVP in the operative setting. (See von Willebrand disease section for more detailed information regarding DDAVP.)

Up to 30% of patients with severe hemophilia A and 3% to 5% of patients with hemophilia B develop an immune response to administered coagulation factors, with the development of IgG antibodies against factor VIII or IX. These antibodies are called inhibitors , and their development is the most significant treatment complication in hemophilia. High titer inhibitors interfere with the infused factor concentrates rendering them ineffective and necessitating the use of costlier and less effective alternative hemostatic agents. Alternative hemostatic agents for patients with an inhibitor include an aPCC or recombinant factor VIIa. The efficacy of these bypassing agents has significant interpatient variation and treatment is complicated with a lack of a clinical dose response relationship and ineffective laboratory methods to monitor efficacy. Because of these limitations, surgical interventions in patients with hemophilia and a high titer inhibitor should be limited to only those procedures deemed medically necessary.

For patients without an inhibitor who are receiving emicizumab prophylaxis, concurrent factor can be used in the setting of surgery to ensure adequate hemostasis. Minor procedures can be completed without additional therapy. Patients with inhibitors who are on emicizumab for prophylaxis and are having surgery should receive rFVIIa. The use of aPCC in combination with emicizumab has been associated with thrombotic events (venous and arterial) and thrombotic microangiopathy. This is hypothesized to be secondary to excessive FIXa from the aPCC that promotes abnormal clotting. In general, aPCC should not be used with emicizumab. If there is a poor clincial response to rFVIIa then aPCC can be used cautiously with recommended dosing <100 U/kg/24 hours.

Ideally, a hematologist should be involved in the perioperative management of patients with hemophilia to help develop an individualized hemostatic plan, consultation for intraoperative hemorrhage complications, and postoperative management.

Clinical Syndromes in Sickle Cell Disease

Children with SCD exhibit a number of clinical syndromes, all of which are caused by aggregation of sickled red cells in small vessels, hemolysis, and decreased survival of abnormal red cells.

Painful vaso-occlusive events are the hallmarks of SCD. Pain results from vascular occlusion and resultant ischemia and can be seen in bony or soft tissues. Precipitating factors include infection, fever, cold exposure, dehydration, venous stasis, and acidosis. Dactylitis, or hand–foot syndrome, is painful swelling of the dorsal surface of the hands and feet caused by vaso-occlusion of the metacarpal and metatarsal bones. It is often the initial clinical manifestation of SCD in the first year of life. Older children typically develop pain crises in the long bones of the arms, legs, vertebral column, and sternum. Pain episodes typically last up to a week and may warrant hospitalization for administration of nonsteroidal antiinflammatory drugs (NSAIDs) and IV opioid analgesics.

Hemolytic anemia becomes apparent at approximately 4 to 6 months of age when the percentage of hemoglobin F diminishes and that of hemoglobin S increases. The anemia of SCD is chronic and well compensated. The chronic hemolysis is responsible for an increased risk for gallstone formation. In general, red cell transfusion is used during life-threatening complications such as aplastic crises, splenic sequestration, ACS, severe symptomatic anemia, or in preparation for major surgery. Chronic transfusion therapy is indicated for patients with severe SCD complications including stroke or recurrent ACS.

Splenic sequestration of sickled red blood cells leads to splenomegaly, acute exacerbation of anemia, and possibly hypovolemic shock. Splenic dysfunction occurs from repeated episodes of splenic infarction during childhood and results in susceptibility to sepsis from encapsulated organisms such as Streptococcus pneumoniae , Neisseria meningitidis , and Haemophilus influenzae . Children with SCD should receive vaccination against these organisms and daily penicillin prophylaxis and prompt evaluation for any fever >38.5°C.

Aplastic crises are typically caused by temporary cessation of red blood cell production in the bone marrow and are most often associated with parvovirus B-19 infection. Symptomatic anemia is treated with hospitalization and red cell transfusion. In addition, during an acute parvovirus infection, patients can have increase SCD complications including pain, splenic sequestration, and acute chest syndrome.

Acute chest syndrome (ACS) is a clinical diagnosis characterized by a new pulmonary infiltrate on chest radiograph associated with one or more clinical symptoms including fever, cough, tachypnea, dyspnea, or hypoxia. The pathophysiology of ACS in SCD is complex and multifactorial and includes infection (bacterial or viral), in situ vaso-occlusion, pulmonary edema, fat embolism, or thromboembolism. General anesthesia is a known risk factor for the development of ACS; therefore, preoperative transfusions are used to reduce this risk. Treatment of ACS includes supplemental oxygen, analgesia, antibiotics, and red cell transfusion to maximize respiratory function and minimize further pulmonary damage. Pulmonary complications account for a large proportion of morbidity and mortality in patients with SCD. During childhood, a substantial number of children with SCD will develop reactive airway disease and progressive pulmonary dysfunction. Up to 40% of adult patients develop moderate to severe pulmonary hypertension, which is associated with an increased mortality rate.

Stroke is one of the most disabling complications of SCD and occurs in approximately 11% of patients before the age of 20 years without screening interventions. The predominant etiology is a large vessel vasculopathy with proliferative intimal hyperplasia. Presenting signs and symptoms include mental status changes, seizures, and focal paralysis (e.g., hemiparesis). Stroke prevention is possible through routine transcranial Doppler imaging, which measures the velocity of cerebral blood flow and detects those children at increased risk for a first stroke. Children with persistently elevated transcranial Doppler measurements are placed on chronic prophylactic red cell transfusions. Children who have a stroke are also placed on a chronic red cell transfusion protocol to minimize the risk for future strokes.

Additional complications of SCD include priapism, retinopathy, leg ulcers, and progressive renal failure. By adolescence the effects of chronic myocardial microvascular obstruction and anemia result in ventricular hypertrophy. Microvascular obstruction of the intestinal circulation results in abdominal crises that manifest as signs and symptoms of an acute abdomen.

The treatment of sickle cell complications includes volume support, administration of antimicrobial agents, and prevention or reversal of anemia, hypothermia, hypoperfusion, acidosis, and pulmonary dysfunction. Hydration decreases blood viscosity and helps prevent capillary stasis. Red cell transfusion is an important aspect of sickle cell treatment because it increases the amount of hemoglobin A, while reducing the proportion of the patient’s own hemoglobin S, which is responsible for sickling. Red cell transfusions are targeted to a hemoglobin level of 10 to 11 g/dL; higher hemoglobin levels will unnecessarily increase blood viscosity. Exchange transfusion to reduce the hemoglobin S level to less than 30% is used in the context of life-threatening episodes such as stroke or severe ACS with pending respiratory failure that does not resolve with simple red cell transfusion.

Hydroxyurea is currently the main drug therapy that is used to prevent SCD complications. Hydroxyurea is thought to mitigate SCD complications through the induction of hemoglobin F production which stabilizes the red cell and prevents sickling. Hydroxyurea should be started at 9 to 12 months of age for all patients with SS or S-Beta-0-thalassemia. A monoclonal antibody (crizanlizumab tmca, Adakveo ) that functions as a p-selectin inhibitor may prevent recurrent pain in patients with all forms of SCD. In a clinical trial of 198 patients, crizanlizumab decreased the annual rate of pain crises by 45% (1.63 versus 2.98) and the duration of hospitalization by 42% (4 versus 6.87 days).

Perioperative Management of Children With Sickle Cell Disease

Historically, patients with SCD have not fared well in the perioperative period. Development of hypoxemia, hypotension, hypothermia, hypovolemia, and acidosis are associated with exacerbation of vaso-occlusive events, and should be prevented. All ongoing medical problems should be optimized before elective surgery. We follow the current National Institute of Health guidelines for perioperative management. Except for short and minor procedures, red cells should be administered to achieve a hemoglobin level of 10 g/dL. If the patient’s baseline hemoglobin is close to 10 g/dL exchange transfusion can be used. Patients with cerebral vasculopathy should have special consideration for anesthesia that maximizes cerebral perfusion. The use of a tourniquet during limb surgery is discouraged because of the possibility of precipitating distal limb hypoxia, hypothermia, and acidosis; however, poor outcomes after tourniquet use have not been reported. When appropriate, regional analgesic techniques are recommended for management of postoperative pain to reduce acute painful crises, to enhance respiratory function, and to minimize opioid use in the postoperative period. Postoperative mortality is often related to development of severe ACS.

Alpha Thalassemias

Hemoglobin Bart’s hydrops fetalis syndrome is the homozygous form of the disease that results in the absence of all four alpha globin chains. This condition results in the fetal overproduction of gamma globin chains (hemoglobin Bart’s) that are incapable of releasing oxygen to the tissues. Severe fetal anemia (hydrops fetalis) develops and is not compatible with intrauterine life unless intrauterine transfusions are instituted. After birth, life-long transfusions are necessary and bone marrow transplantation is curative.

Alpha thalassemia intermedia (hemoglobin H disease) results when three globin chains are absent. Hemoglobin H is the beta-4 tetramer that forms as a result of decreased alpha globin production and relative overproduction of beta globin chains. It is characterized by a mild to moderate microcytic anemia. Patients may develop splenomegaly but only rarely require splenectomy. Alpha thalassemia trait (alpha thalassemia minor) is the heterozygous form of the disease that results in the absence of two globin chains. It is present in approximately 3% of African Americans, and manifests as a microcytic anemia (rarely less than 9 g/dL) that is often confused with mild iron deficiency.

Silent-carrier alpha thalassemia is characterized by the absence of only one globin chain. The hemoglobin concentration and red cell indices are normal.

Beta Thalassemias

Beta thalassemia major (Cooley anemia) is the homozygous form of the disease characterized by the absence of beta globin chains. These children develop a severe anemia and splenomegaly during the first year of life. If the condition is left untreated, bone marrow hyperplasia and extramedullary hematopoiesis produce characteristic features such as tower skull, frontal bossing, maxillary hypertrophy with prominent cheekbones, and an overbite. In the absence of chronic blood transfusions, death occurs within the first few years of life owing to progressive congestive heart failure. A typical treatment regimen will consist of 10 to 15 mL/kg of leukodepleted red blood cells every 3 to 5 weeks to maintain the hemoglobin above 9 to 10 g/dL. Transfusion therapy prevents the clinical manifestations of the anemia but requires concomitant chelation therapy to reverse transfusion-related iron overload.

Thalassemia intermedia is a compound heterozygous state and results in a moderate anemia that does not usually require regular blood transfusions. These patients usually present later in childhood, and may develop clinical manifestations of chronic anemia as seen in thalassemia major. Transfusion therapy is reserved for acute illnesses. Beta thalassemia trait is caused by the absence of one beta chain, and is characterized by an asymptomatic mild microcytic anemia with a hemoglobin level rarely less than 9 g/dL.

Anesthetic management of patients with severe forms of thalassemia (i.e., beta thalassemia major) should focus on ensuring an adequate hemoglobin level before the procedure. Patients with iron overload complicated by cardiac disease (i.e., dilated cardiomyopathy) and/or endocrinopathies (i.e., diabetes, hypothyroidism, hypoparathyroidism) require subspecialty consultation to aid in perioperative management. Patients with alpha or beta thalassemia trait do not require any additional hematologic interventions before surgery.