Abstract
This chapter first addresses the medical, obstetric, and anesthetic considerations for diagnoses that cause anemia in pregnancy. The second half of the chapter reviews the coagulation cascade, the acquired and congenital coagulopathies, how coagulation may be monitored, and how to weigh neuraxial blockade against other anesthetic and analgesic options in the patient with coagulopathy. The chapter closes with a brief review of hypercoagulable states.
Keywords
Anemia, Thalassemia, Sickle cell disease, Thrombocytopenia, Disseminated intravascular coagulopathy, Thrombophilia
Chapter Outline
Anemia, 1088
Normal Hemoglobin Morphology, 1088
Anemia in Pregnancy, 1088
Thalassemias, 1089
Sickle Cell Disorders, 1091
Autoimmune Hemolytic Anemia, 1094
Coagulation, 1094
Thrombocytopenic Coagulopathies, 1097
Autoimmune Thrombocytopenic Purpura, 1098
Thrombotic Thrombocytopenic Purpura, 1099
Inherited Platelet Disorders, 1100
Drug-Induced Platelet Disorders, 1100
Congenital Coagulopathies, 1100
Acquired Coagulopathies, 1102
Disseminated Intravascular Coagulation, 1102
Neuraxial Anesthesia in the Patient with Coagulopathy, 1103
Hypercoagulable States, 1105
Factor V Leiden Mutation, 1105
Prothrombin Gene Mutation, 1105
Antithrombin III Deficiency, 1105
Protein C Deficiency, 1105
Protein S Deficiency, 1105
Lupus Anticoagulant, 1106
Anemia
Normal Hemoglobin Morphology
Normal adult hemoglobin consists of four polypeptides (two alpha and two beta chains) and an iron-containing prosthetic group (heme or ferriprotoporphyrin IX). In the early embryo, theta (θ) and zeta (ζ) chains are present instead of the alpha (α) chains, and epsilon (ε) chains are present instead of the beta (β) chains. After early embryogenesis, pairs of alpha chains are linked with pairs of either beta, gamma (γ), or delta (δ) chains to form adult hemoglobin (Hgb A = α 2 β 2 ), fetal hemoglobin (Hgb F = α 2 γ 2 ), or hemoglobin A 2 (Hgb A 2 = α 2 δ 2 ). By term gestation, the ratio of hemoglobin F to hemoglobin A is approximately 1 : 1. By 1 year of age, hemoglobin F typically constitutes less than 1% of total hemoglobin. Although hemoglobin A 2 is present, it constitutes less than 2.5% of total adult hemoglobin.
The sequence of amino acids (141 amino acids for alpha chains and 146 for beta chains) defines the primary structure; the three-dimensional shape of each chain defines the secondary structure; the relationship between the four chains and the heme prosthetic group defines the tertiary structure; and the binding of the ligands 2,3-diphosphoglycerate (2,3-DPG) and oxygen defines the quaternary structure of the hemoglobin molecule. The physiology of oxygen transport in the fetus is described in Chapter 5 .
Anemia in Pregnancy
During normal pregnancy, plasma volume increases by approximately 50%, but red blood cell (RBC) mass increases by only 30%; this differential increase results in the physiologic anemia of pregnancy (see Chapter 2 ). If the hemoglobin concentration decreases below 10.5 g/dL, the physician should consider other causes of anemia.
Iron deficiency is the most common cause of anemia in pregnancy. It becomes more prevalent as pregnancy advances; in a population-based sample of women in the United States, the prevalence increased from 7% in the first trimester to 14% in the second trimester and 30% in the third trimester of pregnancy. The global incidence is estimated at 19.2%. In addition to reduced hematocrit, iron-deficiency anemia is characterized by low mean corpuscular volume (MCV) and low total serum iron, ferritin, and transferrin saturation.
Iron-deficiency anemia during the first trimester of pregnancy increases the risk for preterm delivery and low birth weight, but evidence is inconclusive for any association between anemia in the second and third trimester and adverse perinatal outcomes. In the United States, the risk for iron deficiency is increased by advanced parity, short interpregnancy interval, Mexican-American ethnicity, and African race. Daily oral iron treatment in pregnancy reduces the risk for maternal anemia, but likely only improves birth outcomes in populations with high rates of anemia and preterm birth. A 2013 meta-analysis of randomized controlled trials identified a dose-response relationship between total daily dose of iron (up to 66 mg/day) and birth weight, but found insufficient evidence of any benefit on the incidence of preterm birth or small-for-gestational age infants. Doses of oral iron also correlate directly with side effects, including nausea, vomiting, constipation, and abdominal cramps. Antepartum anemia is a leading risk factor for postpartum blood transfusion ; however, no study has evaluated the impact of antepartum iron supplementation on the risk for postpartum maternal blood transfusion.
Parenteral (intramuscular or intravenous) iron enhances hematologic response compared with oral iron, but formulations that contain dextran may increase risk for venous thrombosis and allergic reactions.
An elevated hemoglobin concentration (greater than or equal to 14.5 g/dL) has been associated with adverse pregnancy outcomes, including preterm delivery, small-for-gestational-age infants, and stillbirth. In the third trimester of pregnancy, iron overload, as demonstrated by high serum ferritin and low soluble transferrin receptor concentrations, is associated with smaller birth size; consequently, the association between polycythemia and decreased fetal growth can be explained partially, but not exclusively, by inadequate plasma expansion.
Thalassemias
The thalassemias are a group of microcytic, hemolytic anemias that result from the reduced synthesis or dysfunction of one or more of the polypeptide globin chains. This reduced synthesis leads to (1) an imbalance in globin chain ratios, (2) defective hemoglobin, and (3) erythrocyte damage resulting from excess globin subunits. In α-thalassemia, alpha-chain production is reduced, and in β-thalassemia, beta-chain production is reduced. Clinically, thalassemia is divided between transfusion-dependent thalassemia and non–transfusion-dependent thalassemia. Patients with transfusion-dependent thalassemia require ongoing transfusion therapy for survival, but even patients with non–transfusion-dependent thalassemia may require blood transfusions during periods of stress such as infection or pregnancy.
α-Thalassemia
There are two alpha-chain loci on each chromosome 16; therefore, there are four genes that can produce alpha chains. Because deletions or mutations can affect any or all of these genes, four types of α-thalassemia exist: (1) silent carrier (three functioning genes), (2) α -thalassemia trait (two functioning genes), (3) hemoglobin H disease (one functioning gene), and (4) α 0 -thalassemia or Bart’s hydrops (no functioning genes). As the number of functioning genes decreases from three to zero, the ratio of alpha to beta chains decreases from 0.8 : 1 to 0.6 : 1 to 0.3 : 1 to 0 : 1. More than 120 specific genetic mutations have been identified in cases of α-thalassemia, including deletional and nondeletional mutations of the α-globin genes, and mutations in regulatory genes that enhance genetic transcription (e.g., MCS-R2). As beta (or beta-like) chains accumulate, they can form tetramers in utero (hemoglobin Bart’s = γ 4 ) or after delivery (hemoglobin H = β 4 ) and appear as Heinz bodies on the peripheral blood smear.
In the United States, 25% to 30% of black women are silent carriers and have slightly smaller (78 to 85 fL) mean corpuscular volume (MCV) than women without thalassemia. A chromosome lacking one alpha gene is common in Africa, the Mediterranean basin, the Middle East, India, Southeast Asia, Indonesia, and the South Pacific Islands. Silent carriers are not at increased risk for adverse outcome during pregnancy or surgery.
The α -thalassemia trait affects 2% to 3% of black women in the United States and is almost exclusively due to homozygous α+-thalassemia, in which one functional α-globin gene is preserved on each chromosome (α−/α−). These women have an MCV of 70 to 75 fL and mild anemia. They typically are asymptomatic and, beyond the effects of mild anemia, experience no additional risk for adverse outcomes during pregnancy or surgery. Heterozygous α 0 -thalassemia trait (−−/αα) is common among individuals of Southeast Asian descent. It is phenotypically indistinguishable from homozygous α+-thalassemia trait but introduces the risk for bearing an offspring with hemoglobin H disease or Bart’s hydrops.
Patients with hemoglobin H disease experience moderately severe microcytic anemia, splenomegaly, fatigue, and generalized discomfort. Hemoglobin H (β 4 ) constitutes 2% to 15% of the total hemoglobin in these patients. Affected patients generally do not have a decreased life span, and hospitalization for the treatment of their anemia rarely is required. However, disease severity and prognosis vary, depending on the specific mutations present ; some patients have transfusion-dependent thalassemia and require lifelong transfusion and chelation therapy.
Hemoglobin Barts , or α 0 -thalassemia, is generally incompatible with life. The disease is found predominantly in Southeast Asia, China, and the Philippines. Affected individuals die in utero or shortly after birth of hydrops fetalis; mothers carrying these fetuses are prone to develop hypertension or peripartum hemorrhage, or both. Intact neonatal survival has been reported with intrauterine transfusion therapy and postnatal hematopoietic stem cell transplantation. Antenatal screening for the disease is possible (see later discussion).
β-Thalassemias
In β-thalassemia, the production of beta chains is reduced. There are more than 250 genetic causes for ineffective beta-chain production, including gene deletion, transcription mutations, RNA-processing mutations, and mutations that affect protein stability. Unlike the alpha chains, which have four genes (two on each chromosome 16), beta chains have only one gene on each chromosome 11. Severity depends on the combination of mutations present. β 0 -thalassemia, also called β-thalassemia major or Cooley’s anemia, is a transfusion-dependent thalassemia characterized by a complete absence of beta-chain formation. With β + -thalassemia , beta-chain production exists, but either production or function is impaired. For example, Hemoglobin E is a variant of β + -thalassemia in which a point mutation on the β-globin gene both decreases mRNA transcription and decreases affinity between the resulting α- and β-globin proteins. Individuals who receive β-thalassemia genes from both parents but with mutations of different types often develop thalassemia intermedia, and depending on the combination of mutations, may have transfusion-dependent or non–transfusion-dependent thalassemia. Finally, β -thalassemia minor refers to the heterozygous carrier of β-thalassemia, a condition that is not transfusion dependent.
β-thalassemia is found most often in persons from the Mediterranean basin, the Middle East, India, Pakistan, and Southeast Asia and less often among persons from Tajikistan, Turkmenistan, Kyrgyzstan, and China.
Individuals with β-thalassemia have a relative excess of alpha chains that cumulate in RBC precursors. Excess alpha chains undergo auto-oxidation and precipitate to form inclusion bodies called α-hemocromes. Oxidized ferric iron and reactive oxidative species in the α-hemocromes trigger a cascade of events leading to ineffective erythropoiesis and splenic hemolysis. In the fetus, the gamma chain is unaffected; therefore, anemia only develops as gamma-chain production ceases during the first year of life. In some patients, gamma-chain production continues to a variable extent. Thus, the ongoing production of hemoglobin F (even in adults) may minimize the effects of decreased beta-chain production.
β-thalassemia major.
In patients with β-thalassemia major, progressively severe anemia develops beginning in the first few months of extrauterine life. Untreated anemia results in tissue hypoxia, increased intestinal absorption of iron, and increased erythropoietin production. The resulting expansion of marrow cavities causes skeletal abnormalities, extramedullary hematopoiesis, leg ulcerations, osteopenia, and pathologic fractures. Splenomegaly leads to thrombocytopenia and leukopenia. Ineffective erythropoiesis and chronic hemolysis increase the risk for thrombotic complications including venous thrombosis and pulmonary hypertension, with risk particularly elevated among those who have undergone splenectomy. Similar pathology may develop in individuals with thalassemia intermedia, particularly in cases of compound hemoglobin E/β 0 -thalassemia.
RBC transfusions can restore normal childhood development, but the resulting iron load leads to iron accumulation, first in Kupffer’s cells (noncirculating macrophages found in the liver), then in liver parenchymal cells, and finally in endocrine and myocardial cells. Clinical effects of iron overload typically present by the end of the first decade of life. Deposition of iron in endocrine tissues may result in short stature, diabetes mellitus, adrenal insufficiency, hypothyroidism, hypoparathyroidism, and infertility. Pulmonary fibrosis with restrictive disease, and renal dysfunction have been attributed to iron deposition. Myocardial accumulation of iron can lead to conduction abnormalities and intractable heart failure, which are exacerbated by anemia-induced tachycardia. Heart failure and infection are the most common causes of death.
Patients with β-thalassemia major who present when younger than 2 years of age often have hepatomegaly and a hemoglobin concentration as low as 2 g/dL. Patients who present later in life (2 to 12 years of age) typically have a hemoglobin concentration between 4 and 10 g/dL, with marked anisopoikilocytosis and numerous target cells, nucleated RBCs, and inclusion bodies. Levels of hemoglobin F range from 10% to 90% of the total hemoglobin, and hemoglobin A 2 constitutes the remainder of the hemoglobin present.
Treatment includes (1) lifelong transfusion of leukocyte-poor RBCs every 2 to 3 weeks to maintain a hemoglobin concentration greater than 10 g/dL, thus preventing endogenous erythropoiesis; (2) splenectomy; and (3) iron chelation therapy to prevent hemosiderosis. Deferoxamine was the first available chelation agent; it has a long record of successful use, but it requires continuous subcutaneous infusion or intermittent intramuscular injection. Deferiprone and deferasirox are oral chelation drugs. Deferiprone may reduce cardiac iron levels more quickly than other chelation agents, but no studies have demonstrated improved clinical cardiac outcomes. Hematopoietic stem cell transplantation may be curative if a human leukocyte antigen (HLA)-matched family donor without β-thalassemia major is found. Research exploring the potential of gene therapy is underway.
It is unusual for patients with β-thalassemia major to become pregnant; nonetheless, transfusion and chelation regimens improve fertility, and assisted reproductive technologies facilitate conception in women with hemosiderosis-related infertility. The metabolic demands of pregnancy increase transfusion requirements. Mordel et al. reviewed reports of these patients and suggested that up to 8 L of transfused RBCs may be required over the course of pregnancy to maintain the hemoglobin concentration above 10 g/dL. Usually chelation agents are discontinued in pregnancy, given evidence of teratogenicity in animal models and fetal iron depletion described in case reports ; nevertheless, successful pregnancies have been described despite inadvertent use during the first trimester, and some experts suggest resuming chelation therapy in the second and third trimesters among women who develop cardiac symptoms or rapid increase in ferritin.
Historically, these patients had an increased incidence of spontaneous abortion, intrauterine fetal death, and fetal growth restriction (also known as intrauterine growth restriction). A systematic review of case reports and case series identified more than 400 pregnancies complicated by transfusion-dependent β-thalassemia; among women with normal cardiovascular function, careful transfusion therapy and multidisciplinary care appears to facilitate uneventful pregnancy. Although severe skeletal defects and short stature increase the risk for cesarean delivery, trial of labor is usually appropriate, and operative delivery should be reserved for obstetric indications.
In preparation for delivery, careful history and physical examination for the cardiac, pulmonary, hepatic, skeletal, renal, and endocrine manifestations of the disease and complications of iron overload are indicated. Maternal cardiac iron deposition may be quantified using modified magnetic resonance imaging (MRI). Telemetry may be indicated for dysrhythmia surveillance. Heart failure and pulmonary hypertension may be identified using echocardiography. Chronic transfusions increase the risk for alloimmunization, which prolongs the time required to identify compatible allogeneic blood products in the event of peripartum hemorrhage. Intraoperative blood salvage has been safely performed during cesarean delivery in a parturient with thalassemia. Postpartum pharmacologic thromboprophylaxis is indicated.
Craniofacial abnormalities (e.g., maxillary hypertrophy, high arched palate) that increase the risk for difficult airway management may be evident on airway examination. Extramedullary hematopoiesis can result in vertebral cortical weakening, pathologic fractures, and, rarely, paraplegia. However, in the absence of a major pathologic process of the spine, neuraxial anesthesia can be safely administered. Patients with splenomegaly may develop thrombocytopenia; therefore, anesthesia providers should exclude a history of spontaneous hemorrhage and determine the platelet count before initiating a neuraxial procedure.
β-thalassemia intermedia and minor.
The clinical course is usually benign in patients with β-thalassemia minor and with β-thalassemia intermedia when it is not transfusion dependent. The anemia is typically mild (hemoglobin concentration of 9 to 11 g/dL) and is characterized by microcytosis and hypochromatosis. Levels of hemoglobin F range from 1% to 3%, and levels of hemoglobin A 2 range from 3.5% to 7%.
Moderate anemia develops only during periods of stress, such as pregnancy and severe infection. Most patients with non–transfusion-dependent β-thalassemia tolerate pregnancy well, although the incidence of oligohydramnios and fetal growth restriction are greater than in nonthalassemic women. Because of an increased rate of RBC turnover and an increased risk for neural tube defects, high-dose folate supplementation is recommended in the first trimester. Transfusions are reserved for patients with hemorrhage or a hemoglobin concentration below 8 g/dL. Infection, which can cause bone marrow suppression, must be treated promptly. Non–transfusion-dependent β-thalassemia typically does not affect anesthetic management during labor or cesarean delivery.
Antenatal Thalassemia Screening
Among populations at risk for α- or β-thalassemia, antenatal screening can identify couples at increased risk for offspring with a serious hemoglobinopathy. Low maternal and paternal MCV (≤ 80 fL) or mean corpuscular hemoglobin (MCH ≤ 27 pg/cell) with normal serum iron and ferritin should prompt peripheral smear analysis for inclusion bodies, or hemoglobin electrophoresis, or both. The latter test may reveal elevated hemoglobin A 2 or hemoglobin F, suggesting β-thalassemia or another hemoglobinopathy (sickle cell trait [AS], sickle cell anemia [SS], or hemoglobin C trait [SC]). Decreased hemoglobin A 2 suggests hemoglobin H disease; however, α-thalassemia cannot be detected by electrophoresis alone. Focused genetic testing targets known mutations in the population, but rare variants require genome scanning techniques. For β-thalassemia, cell-free fetal DNA obtained from maternal plasma can be used to screen for a paternally inherited mutation that would indicate a 50% risk for fetal disease. Counseling for fetal genetic testing should be offered if both parents carry at least one abnormal hemoglobin gene.
Prenatal diagnosis can be accomplished with the use of fetal cells obtained by means of chorionic villus sampling or amniocentesis and subjected to DNA analysis. In the future, cell-free fetal DNA obtained from maternal plasma may provide an alternative source of material for fetal genetic analysis.
Sickle Cell Disorders
A sickle cell disorder refers to a state in which erythrocytes undergo sickling when they are deoxygenated. Normal erythrocytes have a biconcave shape, whereas sickle cells are elongated and crescent shaped, with two pointed ends. Sickling is attributed to polymorphisms in the β-chains of the hemoglobin molecule. In hemoglobin S, valine is substituted for glutamic acid as the sixth amino acid in the β-chains. This substitution results in a propensity for hemoglobin molecules to aggregate when the hemoglobin is in the deoxygenated state. The hemoglobin molecules stack on top of one another and form microtubules. Hemoglobin C, D, and E are other hemoglobin variants, all characterized by point mutations in the genes that encode the β-chains, and all less prone to sickling than hemoglobin S.
Sickle cell disease refers to disorders in which sickling results in clinical signs and symptoms; it includes hemoglobin SS disease (i.e., sickle cell anemia) and several heterozygous hemoglobinopathies (e.g., sickle cell β 0 -thalassemia, hemoglobin SC disease). Sickle cell disease variants are discussed in the following sections.
Sickle Cell Anemia
Epidemiology.
Table 44.1 lists the prevalence of sickle cell anemia and the other common hemoglobinopathies in the adult black population in the United States. Sickle cell disease is less commonly identified among Hispanic, Middle Eastern, or Asian Indian ethnic groups. The current number of individuals with sickle cell disease in the United States may approach 100,000; high-quality surveillance data are not available.
| Type | Estimated Prevalence |
|---|---|
| Traits | |
| Hemoglobin AS | 1 : 12.5 |
| Hemoglobin AC | 1 : 33 |
| β-Thalassemia minor | 1 : 67 |
| Persistent hemoglobin F | 1 : 1000 |
| Sickling Disorders | |
| Hemoglobin SS | 1 : 625 |
| Hemoglobin SC | 1 : 833 |
| Hemoglobin S–β-thalassemia | 1 : 1667 |
| Hemoglobin S–persistent hemoglobin F | 1 : 25,000 |
| Hemoglobin CC | 1 : 4444 |
| β-Thalassemia major | 1 : 17,778 |
| Hemoglobin C–β-thalassemia | 1 : 4444 |
Pathophysiology.
Oxygen tension is the most important determinant in sickling; other factors that affect sickling are listed in Box 44.1 . Hemoglobin S begins to aggregate at a P o 2 of less than 50 mm Hg (6.7 kPa), and all of the hemoglobin S is aggregated at a P o 2 of approximately 23 mm Hg (3.1 kPa). The formation of hemoglobin S aggregates is time dependent ; the proportion of sickled hemoglobin increases with decreasing cardiac output and prolonged venous transit time. If an erythrocyte sickles, it can return to its normal shape once the hemoglobin becomes oxygenated. However, repeated sickling cycles produce erythrocyte metabolic abnormalities and membrane damage, eventually leading to irreversible sickling regardless of oxygen tension. Sickled cells are cleared rapidly from the circulation by the reticuloendothelial system; as a result, the erythrocyte life span is reduced to approximately 12 days.
- •
Hemoglobin S concentration more than 50% of the total hemoglobin concentration
- •
Dehydration leading to increased blood viscosity
- •
Hypotension causing vascular stasis
- •
Hypothermia
- •
Acidosis
Sickled cells can form aggregates and lead to vaso-occlusive crises and end-organ injury. Repeated cycles of sickling, vaso-occlusion, reperfusion injury, and acute inflammation can lead to chronic inflammation and inflammatory vascular disease. Elevated levels of cell-free hemoglobin deplete nitric oxide, activate the endothelium, and further exacerbate inflammation. The reduced erythrocyte life span results in anemia, jaundice, cholecystitis, and a hyperdynamic hemodynamic state.
Marked ventricular hypertrophy can occur in pregnant women with sickle cell disease secondary to increased cardiac output. This may lead to a decrease in ventricular compliance and a deterioration in ventricular diastolic function. Anemia also leads to erythroblastic hyperplasia, expansion of medullary spaces, and a loss of cortex in long bones, vertebral bodies, and the skull. Vaso-occlusive events can give rise to infarctive crises (which most often occur in the chest, abdomen, back, and long bones), cerebrovascular accidents, and rarely peripheral neuropathy. Aggregate formation in the spleen can result in microinfarcts.
Functional asplenia and abnormal neutrophil responses both contribute to susceptibility to infection. Consequently, the incidence of pneumonia and pyelonephritis is higher in pregnant patients with sickle cell disease than in healthy pregnant patients. Aplastic crises can occur from depression of erythropoiesis secondary to infection (especially parvovirus) or from marrow failure secondary to folate deficiency during pregnancy. During an aplastic crisis, the hemoglobin concentration can decrease rapidly, leading to high-output cardiac failure and death. Sequestration crises can result from the massive pooling of erythrocytes, especially in the spleen. This event occurs more frequently in patients with hemoglobin SC disease or sickle cell β-thalassemia than in patients with other forms of sickle cell disease. In general, a major sequestration crisis is one in which the hemoglobin concentration is less than 6 g/dL and has decreased more than 3 g/dL from the baseline measurement.
The long-term clinical course of sickle cell disease is highly variable. Higher fetal hemoglobin expression and coincident α-thalassemia were among the first genetic modulators described. Subsequent work has identified a complex network of single nucleotide polymorphisms associated with specific complications of sickle cell disease, most prominently the transforming growth factor-beta (TGF-β) family of membrane-bound receptors. These receptors play a role in fibrosis, cell proliferation, hematopoiesis, osteogenesis, angiogenesis, nephropathy, wound healing, and immune response.
Diagnosis.
In the adult, sickle cell anemia is characterized by (1) a hemoglobin concentration of 6 to 8 g/dL, (2) an elevated reticulocyte count, and (3) the presence of sickle cells on a peripheral blood smear. The diagnosis is confirmed by electrophoresis, thin-layer isoelectric focusing, or high-pressure liquid chromatography. Because most hemoglobinopathies are inherited as autosomal recessive conditions, prenatal screening for abnormal hemoglobin is recommended in couples at high risk for sickle cell disease. In utero , the diagnosis can be made through the use of restriction endonucleases specific for the sickle mutation applied to fetal cells obtained during amniocentesis or chorionic villus sampling.
Interaction with pregnancy.
Pregnancy typically exacerbates the complications of sickle cell anemia. Maternal mortality from sickle cell disease composes as many as 1% of all maternal deaths in the United States. Thromboembolic complications, infection, cardiomyopathy, and pulmonary hypertension are the most serious maternal medical complications. Patients with sickle cell anemia have an increased incidence of preterm labor, placental abruption, fetal growth restriction, preeclampsia, and eclampsia. Intensive fetal surveillance may reduce the risk for intrauterine fetal death.
Medical management.
Sickle cell anemia is a chronic anemia; blood transfusions are given only when they are specifically indicated (e.g., acute anemia, aplastic crisis, acute chest syndrome, pneumonia with hypoxemia, before or during surgery). The goals of transfusion are to achieve a hemoglobin concentration greater than 8 g/dL and to ensure that hemoglobin A represents more than 40% of the total hemoglobin present. Systematic review of cohort studies suggests that prophylactic blood transfusions during pregnancy decrease perinatal and maternal mortality, preterm birth, and maternal vaso-occlusive pain episodes, pulmonary complications, and pulmonary embolism ; randomized trials confirm a decrease in the frequency of maternal pain crises, but more evidence is needed to evaluate the other outcomes. If the patient’s baseline hemoglobin concentration is less than 6 to 7 g/dL, simple transfusions with buffy-coat–poor, hemoglobin S–free, washed RBCs should be adequate to meet treatment goals. Otherwise, partial exchange transfusions may be necessary.
Hemoglobin F does not form aggregates with hemoglobin S. Hydroxyurea enhances the production of hemoglobin F, and reduces vaso-occlusive crises and other complications of sickle cell anemia. It is unclear whether hydroxyurea is safe in pregnancy; the drug is known to be carcinogenic, mutagenic, and teratogenic in animals. However, among a small series of pregnancies conceived at the time of maternal or paternal hydroxyurea administration, there was no evidence of abnormal pregnancy outcomes or teratogenicity among surviving offspring. L-glutamine powder was approved by the U.S. Food and Drug Administration in 2017 to reduce acute complications of sickle cell disease, on the basis of a trial that demonstrated decreased rates of vaso-occlusive crisis. Bone marrow transplantation is a potentially curative therapy for individuals with complicated sickle cell disease, although HLA-matched donors can be difficult to locate and the procedure is associated with significant morbidity and mortality.
Obstetric management.
During prenatal visits, the obstetrician should monitor maternal weight gain, blood pressure, urine protein content, and uterine and fetal growth. Antenatal aspirin therapy reduces the risk for preeclampsia (see Chapter 35 ). Maternal surveillance for the complications of sickle cell disease continues throughout pregnancy, and antepartum fetal surveillance begins at the time of extrauterine viability. Finally, pharmacologic thromboprophylaxis is indicated.
Anesthetic management.
Principles of anesthetic management include (1) close surveillance for the complications of sickle cell disease, (2) use of crystalloid to maintain intravascular volume, (3) transfusion of RBCs to maintain oxygen-carrying capacity, (4) administration of supplemental oxygen, (5) maintenance of normothermia, (6) prevention of peripheral venous stasis, and (7) provision of appropriate venous thromboembolism prophylaxis. Preoperative evaluation should focus on recent sickle cell disease exacerbations, the degree of anemia, and chronic end-organ injury. Pulmonary hypertension and high-output heart failure should be excluded with echocardiography. Preoperative blood transfusion to achieve a hemoglobin concentration of 10 g/dL improves perioperative outcomes for nonobstetric sickle cell patients undergoing medium-risk surgery with general anesthesia, but no trial has evaluated prophylactic blood transfusion before cesarean delivery. Early preparation of cross-matched blood products should be considered because alloimmunization, and the antigen cross-matching procedures recommended to prevent its development, can prolong cross-matching procedures. Pain control during labor is essential; continuous neuraxial analgesia is recommended. Although general anesthesia for cesarean delivery has been associated with postoperative sickling complications, either neuraxial or general anesthesia is acceptable, and the choice of anesthetic technique ultimately depends on the time available to induce anesthesia and the patient’s preference and physical status.
Sickle Cell Disease Variants
If a patient carries one hemoglobin S gene and another gene for a hemoglobin that has a propensity to sickle, that patient is considered to have sickle cell disease. Patients with hemoglobin SD disease tend to have the mildest form, and patients with SC disease or sickle cell β-thalassemia tend to have more severe disease.
As with the hemoglobin S gene, hemoglobin C is most prevalent among persons of West African descent, whereas hemoglobin D is distributed among persons of African, northern European, and Indian descent, and hemoglobin E is most prevalent among persons of Southeast Asian descent. Patients with hemoglobin SC and hemoglobin SD disease tend to be asymptomatic during childhood with only mild anemia. Typically, these individuals do not develop symptoms until the second half of pregnancy. During late pregnancy, they may have severe anemia (secondary to splenic sequestration) and splenomegaly. Patients with hemoglobin SC disease also have a tendency to develop bone marrow necrosis, which predisposes to fat emboli. The other clinical manifestations are similar to those observed in patients with sickle cell anemia.
Blood transfusion is recommended only when the hemoglobin concentration is less than 7 to 8 g/dL. Obstetric and anesthetic management are similar to the management of patients with sickle cell anemia.
Patients who are homozygous for hemoglobin C, D, or E typically have mild anemia. Target cells often are observed, and splenomegaly is common. The diagnosis is confirmed with electrophoresis, thin-layer isoelectric focusing, or high-pressure liquid chromatography. Pregnancy typically is well tolerated, and no specific change in obstetric or anesthetic management is required.
Sickle Cell Trait
Sickle cell trait (i.e., hemoglobin SA) occurs in approximately 8% of African-American women in the United States. The RBCs of patients with sickle cell trait do not sickle until the P o 2 decreases below 15 mm Hg (2.0 kPa); therefore, RBC life span is normal. Patients with sickle cell trait are not at increased risk for adverse outcome during surgery or the peripartum period. Nevertheless, sickle cell trait is associated with higher rates of thromboembolic complications, and may contribute to long-term adverse outcomes among African Americans, including renal failure and diabetes.
Likewise, patients who are heterozygous for other hemoglobin variants (i.e., one gene for hemoglobin C, D, or E and one hemoglobin A) are asymptomatic. The heterozygous state for both the thalassemias and the structural hemoglobinopathies appears to protect against malaria, which may explain their geographic distribution and continued presence in the gene pool.
Autoimmune Hemolytic Anemia
Patients with autoimmune hemolytic anemia produce antibodies to their own RBCs, resulting in hemolysis and varying degrees of anemia. The annual incidence of new cases of autoimmune hemolytic anemia is approximately 1 in 80,000 persons, but the prevalence approaches 1 in 5000. Warm antibodies react with RBCs at a temperature of 35° to 40° C, whereas cold antibodies react optimally at a temperature lower than 30° C. Table 44.2 lists the characteristics of the four main types of autoimmune hemolytic anemia. Approximately one-half of cases are idiopathic, with the remainder attributed to malignancies, autoimmune diseases, infections, or drugs.
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