What Are the Considerations for the Perioperative Management in Patients with Hemoglobinopathies?

Common Hemoglobinopathies and Bleeding Disorders: The major hemoglobinopathies seen in the pediatric population are glucose-6-phosphate dehydrogenase deficiency, hemophilia, and sickle cell disease.

Sickle Cell Disease (SCD) is caused by a variant beta-globin gene on chromosome 11 where valine is substituted for glutamine, resulting in instability of the hemoglobin molecule when deoxygenated, causing sickling, hemolysis, and vaso-occlusive crises. Sickling can be caused by hypothermia, hyperthermia, acidemia, dehydration, and poor oxygenation. Vaso-occlusive crises are caused by a combination of inflammation, vascular endothelial adhesion, and platelet dysfunction. Sickled cells occlude microvasculature causing tissue ischemia. Chronic hemolysis is seen in SCD and results in a baseline hemoglobin of 5–9 g/dL.

Chronic SCD may affect a host of systems including pulmonary restrictive lung disease and pulmonary hypertension, stroke, chronic pain, renal abnormalities and avascular necrosis of the bone.

Treatment for severe chronic disease includes hydroxyurea, which increases the concentration of fetal hemoglobin, causing a leftward shift in the oxyhemoglobin dissociation curve (Figure 9.1). Preoperatively (except with minor, non-invasive procedures), most children with homozygous sickle type hemoglobin (HbSS) should receive a transfusion to correct their hemoglobin level to 10 g/dL and may likely require preoperative hydration, however follow up with the hematologist would be beneficial for specific recommendations.

Figure 9.1 Oxyhemoglobin dissociation curve for fetal and adult hemoglobin.

Illustration by Adam C. Adler, MD

Perioperative considerations in children with SCD include: Preoperative evaluation and management has been shown to reduce peri-anesthetic morbidity and mortality. Avoidance of hypoxia, acidosis, hyperthermia, hypothermia, and dehydration is paramount to minimizing vaso-occlusive crises. Recommendations for transfusions with most patients with SCD are to correct the anemia to around 10 g/dL. Regional anesthetics are beneficial in reducing pain which can promote sickling.

Thalassemia is a common genetic disorder resulting from a disturbance of the 1:1 alpha:beta polypeptide chains. Severity may range from an asymptomatic carrier to hydrops fetalis, resulting in death. Release of toxic agents causes an alteration of red cell membranes resulting in cells that are rigid and can disintegrate. Clinically, patients may need increased erythropoiesis and, transfusions, and may have iron overload as a result. Concomitantly, infections, splenomegaly, and bone abnormalities may be seen as a result of extramedullary hematopoiesis. Patients with chronic severe disease may require splenectomies, cholecystectomies, or vascular access placement for frequent transfusions.

von Willebrand Disease (vWD) is the most common bleeding disorder, seen in 1/10,000 people. The missing or poorly functioning glycoprotein vWF in this disease causes adherence of platelets to the sub-endothelium and inability to carry factor VIII properly. Typical symptoms include easy bruising, epistaxis, and menorrhagia. Type 1 (85% of cases) and type 3 (5% of cases) vWD are quantitative deficiencies, while type 2 (10% of cases) is both a qualitative and quantitative deficiency of vWF multimers.

Typical coagulation studies (PT/aPTT) may be normal in patients with vWF, especially if factor VIII is normal. DDAVP is effective in type I to stimulate the release of vWF; however, it can be deleterious in type II as it may increase the level of poorly functioning vWF. Intravenous fluid hydration should be minimized after administration of exogenous factors to avoid diluting the functional factor. Additionally, acquired vWF may be seen with lymphoproliferative disorders, chronic renal failure, Wilms tumor, hypothyroidism, and certain congenital heart diseases. Caution should be used when considering regional anesthesia, intramuscular injections, nasogastric tubes, and nasal intubations. Consideration may be given to use of antifibrinolytic agents such as aminocaproic acid and tranexamic acid.

Treatment can involve use of DDAVP to encourage release of endogenous stores (types 1 and 3 only) or through use of plasma-derived factor VIII-vWF concentrates (Humate-P).

Hemophilia: Hemophilia A is a congenital bleeding disorder caused by a deficiency in factor VIII, while Hemophilia B is caused by a deficiency in factor IX; each of these bleeding disorders has wide ranges of penetrance, so mild disease may not be noted unless severe trauma occurs, while severe disease may be seen spontaneously even with minor trauma. The degree of the disease depends on the percentage of functional factor. Because hemophilia is typically X-linked, female carriers have 50% of normal factor concentrations, so they are typically asymptomatic. DDAVP may be helpful in mild cases to increase the factor VIII availability, while recombinant factor VIII may be required in other situations. Recommendations from hematology should be obtained to identify the optimal perioperative management strategy. The goal of treatment in a patient with hemophilia undergoing a surgical procedure is to obtain a factor level of 0.8–1.0 units/mL (80–100%) prior to the surgical procedure.

Patients with mild to moderate hemophilia are generally only treated prior to surgical procedures. In general, for non-life-threatening bleeding, coagulation factor activity should be raised to 40–50% of normal. For life-threatening bleeding, coagulation factor activity is raised to 80–100% of normal.

Factor replacement is continued into the postoperative period; 2–3 days after a minor procedure and 7–10 days for major procedures, especially in situations where bleeding is highly detrimental (neurological surgery). Intermittent dosing or continuous infusion factor replacement can be used to accomplish this goal.

Dose of Factor VIIIUnits=Desired Rise in%Factor Activity×Weightkg×0.5

Dose of Plasma−derived FactorIXUnits=Desired Rise in%Factor Activity×Weightkg×1

Pediatric dose of recombinant FactorIXUnits=DesiredRisein%Factor Activity×Weightkg×1.4

Adult dose of recombinant FactorIXUnits=Desired Rise in%Factor Activity×Weightkg×1.2

*Dosing for modified prolonged half-life products will depend on the specific product and the patient’s pharmacokinetics.

What Are the Indications for Transfusion in the Perioperative Setting?

According to the American Society of Anesthesiology Task Force on Blood Component Therapy, there is evidence to suggest that transfusion at a hemoglobin above 10 g/dL is not indicated, and that transfusion is indicated for lab values below 6 g/dL. For hemoglobin between 6 and 10 g/dL, decision to transfuse should be made based on the child’s clinical picture, including vital signs, efficiency of oxygenation and perfusion, as well as degree of blood loss. Transfusion may still be indicated in a child with a Hb >10 g/dL if the clinical picture drives an indication such as baseline increased Hb, increased oxygen demand, higher concentrations of Fetal Hb, or other surgical components.

What Are the Risks of Transfusion for Preterm Infants?

Significant risks include hyperkalemia and hypocalcemia. Consideration should be made to receive the freshest blood from the blood bank to minimize hyperkalemia. Often a single unit is split into multiple units over a period of time for a preterm infant, so care should be taken to ensure that the split units are administered from the same “original unit” to minimize exposure of the baby to multiple donors.

For a preterm infant, acute blood loss risks include hypovolemia, hypotension, acidosis, apnea, and hyperkalemia.