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 and oxygen defines the quaternary structure of the hemoglobin molecule. The physiology of oxygen transport across the placenta and in the fetus is described in Chapters 4 and 5 .
Anemia in Pregnancy
During the course of normal pregnancy, plasma volume increases by approximately 50%, but red blood cell mass increases by only 30%; this differential increase results in the physiologic anemia of pregnancy (see Chapter 2 ). It is important to distinguish between physiologic and pathologic anemia. Pregnant women at sea level with hemoglobin < 11 g/dL (hematocrit < 33%) in the first and third trimesters, and < 10.5 g/dL (hematocrit < 32%) in the second trimester should be considered anemic. The global prevalence of pathologic anemia in pregnant women is estimated to be 36.5% (95% uncertainty interval, 34.0% to 39.1%).
Iron deficiency is the most common cause of anemia in pregnancy. It becomes more prevalent as pregnancy advances. 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. Serum ferritin remains the most sensitive marker for iron-deficiency anemia.
Iron-deficient mothers experience an increased incidence of preterm delivery, low birth weight, and small-for-gestational-age infants, all of which are associated with poorer neurodevelopment outcomes, although it is uncertain the degree to which this link is causal. Low maternal hemoglobin is also associated with a range of adverse maternal outcomes, including postpartum hemorrhage, preeclampsia, transfusion, postnatal depression, and maternal mortality.
In the United States, the risk for iron deficiency is increased by advanced parity, short interpregnancy interval, Mexican American ethnicity, and African-American 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 metaanalysis 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. In a 2019 metaanalysis, intravenous iron was superior to oral iron for treatment of iron-deficiency anemia in pregnancy. Women receiving intravenous iron achieve desired hemoglobin targets faster and with fewer side effects. However, parenteral iron formulations that contain dextran may increase the risk for venous thrombosis and allergic reactions.
Severe antepartum anemia increases the risk of peripartum blood transfusion and postpartum hemorrhage. However, it is unclear if antepartum iron supplementation reduces the risk for postpartum maternal transfusion. In a single-center quality improvement study, implementation of a standardized treatment protocol for the management of antepartum anemia was associated with increased intravenous iron utilization and predelivery hemoglobin. However, no significant difference between the pre- and postimplementation groups in blood product transfusion was observed.
High maternal hemoglobin (≥13.0 g/dL) is associated with increased odds of adverse infant outcomes (very low birth weight, preterm birth, small for gestational age, and stillbirth) and adverse maternal outcomes (preeclampsia, gestational diabetes, and maternal mortality). 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. Further research is needed to define optimal hemoglobin thresholds during pregnancy.
Thalassemias
The thalassemias are a group of recessively inherited hemoglobinopathies 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 syndromes are divided into transfusion-dependent thalassemias and non–transfusion-dependent thalassemias . Patients with transfusion-dependent thalassemia require ongoing transfusion therapy for survival, but even patients with nontransfusion-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. Deletions or mutations can affect any or all of these genes resulting in four types of α-thalassemia: (1) silent carrier (three functioning genes), (2) α -thalassemia trait/minor (two functioning genes), (3) hemoglobin H disease (one functioning gene), and (4) α 0 -thalassemia major or hemoglobin 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. The depletion of alpha chains leads to a surplus of beta or beta-like globin chains. In the fetal and early postnatal period, the surplus γ-globin chains form tetramers (hemoglobin Bart’s = γ 4 ) later replaced by β-tetramers (hemoglobin H = β 4 ) as beta-globin synthesis increases after delivery.
In the United States, 25% to 30% of Black women are silent carriers and have slightly smaller MCV than women without thalassemia. Silent carriers are not at increased risk for adverse outcomes during pregnancy or surgery.
The α-thalassemia trait is common among individuals of African, Southeast Asian, West Indian, Middle East, and Mediterranean ancestry. Those of Southeast Asian descent are more likely to carry two gene deletions in cis or on the same chromosome (−−/αα). This is associated with an increased risk for bearing offspring with hemoglobin H disease or Bart’s hydrops. α-Thalassemia trait affects 2% to 3% of Black women in the United States, , and is almost exclusively a result of deletion of a single α-globin gene on each chromosome 16 (α−/α−). Due to this gene deletion in trans (α−/α−), hemoglobin Bart’s disease does not typically develop in fetuses of α-thalassemia carriers of African descent. Women with the α-thalassemia trait typically have a mild asymptomatic microcytic anemia (MCV of 70 to 75 fL) and experience no additional risk for adverse outcomes during pregnancy or surgery.
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 is rarely 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 Bart’s hydrops, 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.
β-Thalassemias
In β-thalassemia, the production of beta chains is reduced. There are more than 400 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. The disease severity depends on the combination of mutations present; there are three main clinical presentations.
β 0 -thalassemia , also called β-thalassemia major or Cooley anemia , is a transfusion-dependent thalassemia characterized by a complete absence of beta-chain formation.
In β + -thalassemia or thalassemia intermedia , there is formation of beta chains 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 decreases mRNA transcription and decreases affinity between the resulting β-globin proteins and the α-chains. Thalassemia intermedia is a spectrum and, depending on the inherited combination of mutations, individuals may have transfusion-dependent thalassemia or nontransfusion-dependent thalassemia.
Finally, β – thalassemia minor refers to the heterozygous carrier of β-thalassemia and 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 red blood cell precursors. Excess alpha chains undergo autooxidation 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 persistent production of hemoglobin F (even into adulthood) may minimize the effects of decreased beta-chain production.
β-Thalassemia major
Progressively severe anemia develops beginning in the first few months of extrauterine life in patients with β-thalassemia major. 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.
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 red blood cells, 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.
The mainstay of conventional treatment is transfusion combined with iron chelation therapy . Patients require transfusions of red blood cells (preferably leukocyte-depleted) every 2 to 4 weeks with the goal of maintaining hemoglobin between 9.0 and 10.5 g/dL, or 11.0 and 12.0 g/dL for patients with cardiac disease. Patients with transfusion-dependent thalassemia receiving regular transfusions invariably develop iron overload because the human body lacks a mechanism to excrete excess iron.
The resulting iron load accumulates, 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.
There are three iron chelators currently licensed for clinical use. Deferoxamine was the first available chelation agent. It has a long record of successful use but 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.
Emerging therapies in thalassemia can be classified into three major categories based on their efforts to address different features of the underlying pathophysiology of β-thalassemia: (1) correction of the globin chain imbalance, (2) addressing ineffective erythropoiesis, and (3) improving iron overload.
The rationale for bone marrow transplantation for a patient with transfusion-dependent β-thalassemia is to restore the tissue’s capability of producing functional hemoglobin. Hematopoietic stem cell transplantation may be curative if a human leukocyte antigen (HLA)-matched family donor without β-thalassemia major is found. The main limitations to this form of therapy include the need for a suitable donor, patient fitness, and procedure-related toxicity.
Research exploring gene therapy as a mechanism for correcting globin chain imbalance is still underway. In addition, multiple clinical trials are investigating molecules that target ineffective erythropoiesis or undo iron dysregulation.
Historically, it was unusual for patients with β-thalassemia major to become pregnant. Hypogonadotropic hypogonadism is the most frequent endocrinopathy in thalassemia major; patients are predisposed to develop pubertal failure, sexual dysfunction, infertility, and short stature. Advances in care by optimizing transfusion and chelation regimens have improved 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 in 1989 and suggested that up to 8 L of transfused red blood cells may be required over the course of pregnancy to maintain the hemoglobin > 10 g/dL. Almost 20 years later, Origa et al. summarized the clinical course of 46 women with thalassemia major (58 pregnancies), followed for 11 years. Multidisciplinary management led to safe pregnancies and favorable outcomes for most of the pregnancies. Chelation agents are usually discontinued in pregnancy, given evidence of teratogenicity in animal models and fetal iron depletion described in case reports. However, successful pregnancies have been described despite inadvertent chelation agent use during the first trimester, and some experts suggest resuming chelation therapy in the second and third trimesters in women who develop cardiac symptoms or rapid increase in ferritin.
Historically, patients with β-thalassemia major had an increased incidence of spontaneous abortion, intrauterine fetal growth restriction, and intrauterine fetal death. A systematic review of case reports and case series over a period of 17 years identified 417 pregnancies complicated by transfusion-dependent β-thalassemia. There were two maternal deaths. 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, a trial of labor is usually appropriate as thalassemia in itself is not an indication for operative delivery.
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. 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 generally 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 β-thalassemia intermedia who are not transfusion dependent. The anemia is typically mild (hemoglobin concentration of 9 to 11 g/dL) and is characterized by microcytosis, hypochromasia, and levels of hemoglobin A 2 > 3.5%.
Moderate anemia develops during periods of stress, such as pregnancy and severe infection. Most patients with nontransfusion-dependent β-thalassemia tolerate pregnancy well, although the incidences of oligohydramnios and fetal growth restriction are greater than in women without thalassemia. A 2023 study also reported a higher incidence of pregnancy-induced hypertension in the β-thalassemia trait group compared to a control group. Because of an increased rate of red blood cell turnover and an increased risk for neural tube defects, high-dose folate supplementation is recommended in the first trimester. Maternal anemia influences birthweight and preterm delivery. Therefore, the aim should be to maintain maternal hemoglobin > 10 g/dL to allow normal fetal growth.
Women with nontransfusion-dependent thalassemia who have never previously been transfused or who have received only minimal transfusion therapy are at risk of severe alloimmune anemia if blood transfusions are required during pregnancy. To minimize this risk, extended genotype and antibody screening should be performed before administering any transfusions during pregnancy. If transfusion becomes necessary, fully phenotype-matched blood should be administered. Infection, which can cause bone marrow suppression, must be treated promptly. Nontransfusion-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 serious hemoglobinopathy. Low maternal and paternal MCV (≤80 fL) or mean corpuscular hemoglobin (≤27 pg/cell) with normal serum iron and ferritin is an indication for a peripheral smear analysis for inclusion bodies, hemoglobin electrophoresis, or both. β-thalassemia is associated with elevated HbF and elevated HbA 2 (>3.5%) levels. Decreased HbA 2 suggests hemoglobin H disease. However, hemoglobin electrophoresis cannot reliably detect individuals with α-thalassemia trait; this requires molecular genetic testing. 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. The use of noninvasive prenatal diagnosis using cell-free fetal DNA obtained from maternal plasma is still experimental and is not yet recommended.
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; all are 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 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 is estimated to approach 100,000, but high-quality surveillance data are not available.
Table 44.1
Prevalence of Hemoglobinopathies in the United States in Persons of African Descent
Modified from Motulsky AG. Frequency of sickling disorders in U.S. blacks. N Engl J Med . 1973;288:31–33.
| 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 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.
Box 44.1
Factors That Increase Sickling in Women With Sickle Cell Anemia
-
•
Hemoglobin S > 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 potentially 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. 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 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 adults, 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 contributes to 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 > 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 red blood cells 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 US Food and Drug Administration (FDA) 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 should continue throughout pregnancy, and antepartum fetal surveillance begins at the time of extrauterine viability (see Chapter 6 ). Finally, pharmacologic thromboprophylaxis is indicated both during pregnancy and postpartum.
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 red blood cells 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 patients with sickle cell disease 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 hemoglobin SC disease or sickle cell β-thalassemia disease 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. 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 tend 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 managing 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 red blood cells of patients with sickle cell trait do not sickle until the P o 2 decreases below 15 mm Hg (2.0 kPa); therefore, red blood cell 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-American people, including renal failure and diabetes.
Likewise, people 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 red blood cells, 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 red blood cells at a temperature of 35°C to 40°C, whereas cold antibodies react optimally at a temperature < 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.
Table 44.2
Characteristics of Autoimmune Hemolytic Anemias
From Gibson J. Autoimmune hemolytic anemia: current concepts. Aust NZ J Med . 1988:18:625–637; Engelfriet CP, Overbeeke MA, von dem Borne AE. Autoimmune hemolytic anemia. Semin Hematol . 1992;29:3–12.
| Disease | Immunoglobulin (Ig) | Complement Involved | Site of Red Blood Cell Destruction | Treatment | Transfusion Requirements |
|---|---|---|---|---|---|
| Incomplete warm autoantibodies |
|
|
|
Corticosteroids, splenectomy, immune globulin | Rarely needed; if given, combined with corticosteroids |
| Complete warm autoantibodies | |||||
| Type 1 | IgM | C4b and C3b | Liver | Corticosteroids, splenectomy | Rarely needed |
| Type 2 | IgM | C1–C9 | Intracellular | Plasma exchange, corticosteroids | Frequently needed |
| Cold autoagglutinins and hemolysins | IgM | No | Intracellular | Corticosteroids, keeping patient warm | Very rarely needed |
| Biphasic hemolysins | |||||
| Acute | IgG | Yes | Intracellular agglutination | Treatment of underlying infection | Occasionally needed |
| Chronic | IgG | Yes | Intracellular hemolysis | Plasmapheresis, chlorambucil | Frequently needed |
IgA , Immunoglobulin A; IgG , immunoglobulin G; IgM , immunoglobulin M.
Patients with warm-reacting antibodies typically respond to treatment with corticosteroids; splenectomy and the anti-CD20 antibody rituximab are second-line therapies. After splenectomy, relapses and blood transfusions may lead to the continued requirement for intermittent or continuous corticosteroid therapy. The presence of the antibody and the requirement for extended phenotyping may delay matched blood product availability. In acute hemorrhage, the rapid transfusion of body-temperature, ABO-compatible and Rh-negative blood can be lifesaving, with the expectation that the half-life of transfused red blood cells will be shortened; this practice will allow time to procure compatible blood products.
In patients with cold-reacting antibodies , the anemia typically is mild, and maintenance of normal body and ambient temperatures typically is all that is required to prevent hemolysis.
COAGULATION
Thrombotic and Thrombolytic Pathways
Hemostasis depends on the normal function of vascular tissue, platelets, and coagulation factors. During the initial response to loss of vessel integrity, platelets adhere to exposed collagen, facilitated by the von Willebrand factor (vWF) (primary hemostasis). Platelet activation results in the release of substances that constrict the injured vessels and cause other platelets to adhere and form a hemostatic plug. The platelet plug is not stable, and initiation of the coagulation cascade, followed by deposition and stabilization of fibrin, is necessary for definitive hemostasis (secondary hemostasis). Most coagulation factors circulate in the blood as zymogens, which are converted to active enzymes that in turn convert other zymogens to active enzymes. For example, factor X (a zymogen) is converted to factor Xa (an enzyme), which converts prothrombin (factor II) to thrombin (factor IIa).
In its original conception, the coagulation cascade ( Fig. 44.1 ) was believed to propagate within plasma. Subsequent work located the enzymatic reactions of the extrinsic system primarily to the surface of subendothelial cells and those of the intrinsic system to the activated platelet surface. Currently, a widely used model divides the coagulation cascade into three phases: (1) an initiation phase (classical extrinsic pathway), in which small amounts of active coagulation factors are generated; (2) an amplification phase , in which the level of active coagulation factors is boosted; and (3) a propagation phase , in which coagulation factors bind to the membrane of activated platelets, leading to the formation of fibrin clots.
Components of the Extrinsic, Intrinsic, and Common Pathways and the Fibrinolytic System. The term cascade is a misnomer that stems from the presence of positive and negative feedback loops in both the coagulation and fibrinolytic systems. PF3 , Platelet factor 3; t-PA , tissue plasminogen activator.
In the classic extrinsic pathway, tissue damage activates tissue factor (TF) (also known as factor III or thromboplastin) on the surface of extravascular cells (e.g., fibroblasts, smooth muscle cells), which are exposed to the bloodstream after tissue damage. TF has also been identified on the surfaces of syncytiotrophoblasts, adhered leukocytes, circulating monocytes, and circulating microparticle membrane vesicles released by inflammatory and tumor cells. TF binds factor VII and promotes proteolysis and activation to factor VIIa. On the membrane surface, the TF/VIIa complex converts factor X to Xa and small amounts of factor IX to IXa. Factor Xa amplifies conversion of factor VII to VIIa in the first of many positive feedback loops, and factor Xa forms a complex with factor Va. The membrane-bound prothrombinase complex (i.e., Xa/Va) converts small amounts of soluble prothrombin to thrombin. This thrombin diffuses to the activated platelet surface, where it amplifies the intrinsic coagulation pathway.
In the intrinsic pathway, factor XII binds to a negatively charged substrate (e.g., collagen, platelet phosphatidylserine) and may undergo autolysis to form factor XIIa, or it may be converted to XIIa by trace amounts of XIIa. In addition to activating its own zymogen, factor XIIa converts prekallikrein to kallikrein and factor XI to XIa. High-molecular-weight kininogen can bind factor XI and facilitate its conversion to XIa by XIIa. Kallikrein and high-molecular-weight kininogen also can convert factor XII to XIIa. Factor XIa converts factor IX to IXa, which, with cofactor VIIIa, converts factor X to Xa.
Factor Xa promotes platelet aggregation and it converts factors V and VIII to factors Va and VIIIa, respectively. Factor Xa, combined with cofactor Va, converts factor II (prothrombin) to factor IIa (thrombin), a process termed the thrombin burst . Activated platelets provide the primary surface for conversion of factor X to Xa and prothrombin to thrombin. Thrombin converts factors I (fibrinogen), V, VIII, and XIII to factors Ia (fibrin), Va, VIIIa, and XIIIa, respectively. Thrombin also causes platelet activation. Factor XIIIa is required to cross-link fibrin strands, which helps form a stable clot.
Clot formation is limited by the natural anticoagulants antithrombin III, protein C, and tissue factor pathway inhibitor (TFPI). Protein S is a cofactor for protein C and TFPI. Activated by a thrombin-thrombomodulin complex, activated protein C with cofactor protein S breaks down factors Va and VIIIa. TFPI is produced by endothelial cells and inhibits coagulation by binding both factor Xa and the TF/factor VIIa complex. TPFI-2 is produced by placental syncytiotrophoblasts and appears to act as an anticoagulant within the intervillous space. Antithrombin III, whose activity is enhanced by heparin, inhibits factor IXa, factor Xa, and thrombin.
The final component of the coagulation system is the fibrinolytic system , in which plasmin breaks down fibrin. The precursor for plasmin is plasminogen, which is synthesized in the liver. Tissue-type plasminogen activator (t-PA) circulates as an active protease; its activity increases dramatically when it binds to fibrin, at which time it converts plasminogen to plasmin. Endothelial cells secrete urokinase-like plasminogen activator as the relatively inactive prourokinase; it is converted to the active form (single-chain urokinase) by plasmin. Single-chain urokinase is converted to its most active form (double-chain urokinase) by kallikrein, which is released during activation of the coagulation cascade.
Plasmin-mediated fibrinolysis is confined to the clot by the local availability of fibrin and by plasminogen activator inhibitor-1 (PAI-1), which is secreted by many cells, and by plasminogen activator inhibitor-2 (PAI-2), which is secreted primarily by the placenta. Alpha 2-antiplasmin (α2AP) is synthesized in the liver and binds circulating plasmin, but not plasmin bound to fibrin. Within immature thrombi, factor XIIIa cross-links α2AP to fibrin. Additional antifibrinolytic mechanisms protect hemostatic thrombi from early dissolution. Thrombin-activatable fibrinolysis inhibitor (TAFI) is synthesized in the liver, is activated by the thrombin-thrombomodulin complex, and inhibits fibrinolysis by eliminating the binding sites on fibrin for plasminogen and t-PA. The antifibrinolytic drugs tranexamic acid and aminocaproic acid inhibit fibrinolysis by binding to plasminogen and plasmin and preventing their binding to fibrin.
Changes in the concentrations of coagulation factors during pregnancy are outlined in Chapter 2 (see Box 2.2 ). The levels of most procoagulants increase during pregnancy, while anticoagulant levels remain stable or decrease. Although t-PA levels decrease and antifibrinolytic proteins (i.e., PAI-1, PAI-2, TAFI, α2AP) increase, plasminogen and fibrin degradation product levels increase, suggesting that fibrinolysis continues unabated during pregnancy.
Placental syncytiotrophoblasts promote coagulation by presenting TF and phospholipids to maternal blood coursing through the intervillous space. The concentrations of the thrombin-antithrombin complex and fibrin degradation products are elevated in blood from the uterine vein compared with peripheral blood, suggesting that many of the hemostatic changes of pregnancy originate in the placental bed.
Deficiencies in procoagulant factors or an increase in fibrinolytic factors cause hemorrhagic disorders . Deficiencies in antithrombin III, protein C or S, or the fibrinolytic system cause thromboembolic disorders .
Assessment of Coagulation
Routine Hematology
The increase in the concentration of most coagulation factors is associated with a shortening of the prothrombin time (PT) and the activated partial thromboplastin time (aPTT) during normal pregnancy, although values remain within the nonpregnant normal limits. Similarly, fibrinogen and fibrin degradation products are increased. These changes may mask the early diagnosis of disseminated intravascular coagulation (DIC) , so serial laboratory parameters are indicated if the diagnosis is suspected. Thrombocytopenia is a sensitive, but not specific, indicator of DIC. For women with severe preeclampsia, a platelet count is a clinically useful screening test; a result below 100,000/µL suggests the possibility of impairment of other coagulation parameters. In the healthy parturient with no history or clinical signs of bleeding, the routine laboratory assessment of hemostasis parameters, including platelet count, is not indicated prior to the initiation of a neuraxial anesthetic procedure.
Whole-Blood Viscoelastic Testing
Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) measure whole-blood coagulation and provide information about the adequacy of platelet function and other coagulation factors. Both assays generate a graphic representation of clot strength ( Fig. 44.2 ) in which specific parameters are interrelated and reflect activities of coagulation proteins, platelets, and their interaction. Commonly used TEG and ROTEM parameters are defined in Table 44.3 . Activators added to the whole blood can be used to accelerate clotting and to isolate specific components of coagulation ( Table 44.4 ).
Normal Thromboelastomeric Tracing Using the Rotational Thromboelastometry (ROTEM) Extrinsically Activated Thromboelastometric (EXTEM) Assay. A , Current amplitude; Alpha , α-angle; A5, A10, and A15 , amplitude at specific minute interval; CFT , clot formation time; CT , clotting time; MCF , maximum clot firmness.
From Katz D, Beilin Y. Disorders of coagulation in pregnancy. Br J Anaesth . 2015;115(suppl 2):ii75–ii88.
Table 44.3
Commonly Used Thromboelastography and Thromboelastometry Parameters
Modified from Katz D, Beilin Y. Disorders of coagulation in pregnancy. Br J Anaesth . 2015;115(suppl 2):ii75–ii88.
| Coagulation Process | Key Components Tested | TEG | ROTEM | Definition |
|---|---|---|---|---|
| Clotting factor activation | Soluble coagulation factors, tissue factor | R (reaction time, min) | CT (clotting time, min) | Time to amplitude of 2 mm |
| Factor amplification and fibrin cross-linkage | K (kinetics time, min) | CFT (clot formation time, min) | Time for amplitude to increase from 2 to 20 mm | |
| α-angle (degrees) | α-angle (degrees) | Angle between the line in the middle of the graph and the tangential line of the body of the graph | ||
| Clot strength | Fibrinogen, platelets, Factor XIII | A5, A10, A15 (mm) | A5, A10, A15 (mm) | Amplitude measured at specific time points after CT or R (e.g., A5 is at 5 min) |
| MA (maximum amplitude, mm) | MCF (maximum clot firmness, mm) | Maximum amplitude reached | ||
| Clot lysis | Fibrinolytic enzymes, fibrinolysis inhibitors, Factor XIII | LY30 (lysis) | LI30 (lysis index) | % of decrease in MA or MCF 30 min after MA or MCF has been reached |
| EPL (estimated percent lysis) | ML (maximum lysis, %) | Maximal reduction in clot firmness after MA or MCF |
ROTEM , rotational thromboelastometry; TEG , thromboelastography.
Table 44.4
Additives Used in Common Viscoelastic Assays to Isolate Components of the Coagulation System
Modified from Solomon C, Collis RE, Collins PW. Haemostatic monitoring during postpartum haemorrhage and implications for management. Br J Anaesth . 2012;109:851–863.
| TEG-Based Tests | ROTEM-Based Tests | Purpose | ||
|---|---|---|---|---|
| Test | Activators | Test | Activator | |
| Kaolin-activated TEG | Kaolin | INTEM | Ellagic acid | Reveals defects in intrinsic pathway |
| Rapid TEG | Kaolin + tissue factor | Reveals defects in intrinsic and extrinsic pathways; tissue factor accelerates results | ||
| EXTEM | Tissue factor | Reveals defects in intrinsic pathway; reveals platelet deficiency when compared with FIBTEM | ||
| Functional fibrinogen test | Tissue factor + abciximab | FIBTEM | Tissue factor + cytochalasin D | Addition of a platelet inhibitor reveals fibrin-based clot defects—fibrinogen deficiency |
| APTEM | Tissue factor + aprotinin | Aprotinin blocks fibrinolysis; comparison with EXTEM confirms fibrinolysis | ||
APTEM , Aprotinin-based thromboelastometry; EXTEM , extrinsically activated thromboelastometry; FIBTEM , fibrin-based thromboelastometry; INTEM , intrinsically activated thromboelastometry; ROTEM , rotational thromboelastometry; TEG , thromboelastography.
Investigations using viscoelastic monitoring confirm that pregnancy is a hypercoagulable state. Reference ranges for normal values likely vary over the course of pregnancy and into the postpartum period. TEG and ROTEM have been proposed to assess coagulation status in normal and high-risk pregnant women, to assess hemostasis before the initiation of neuraxial anesthesia in high-risk patients, and to monitor the efficacy of venous thromboembolism prophylaxis. Whether viscoelastic monitoring improves clinical outcomes in these contexts is unknown.
Observational data suggest that viscoelastic monitoring may reduce consumption of blood products when used to guide resuscitation for postpartum hemorrhage (see Chapter 37 ). In general, deficits in clotting factor activation, amplification, and fibrin cross-linkage may be corrected with plasma. Deficits in clot strength reflect the need for platelets or fibrinogen (either cryoprecipitate or fibrinogen concentrate). The fibrin-based thromboelastometry (FIBTEM) and functional fibrinogen assays add a platelet inhibitor (cytochalasin D or abciximab) to isolate the need for fibrinogen. For example, a FIBTEM A5 value < 10 mm corresponds to a fibrinogen concentration < 200 mg/dL. Evidence of clot lysis (LY30 > 3% or ML > 15%) supports the need for antifibrinolytic therapy.
Platelet Function Analyzer
The PFA-100 (Siemens Healthcare Diagnostics, Deerfield, IL) measures platelet function in vitro , especially platelet activation and aggregation. This simple test evaluates the capacity of a sodium-citrated whole-blood sample to form a platelet plug at the aperture situated on a collagen/adenosine phosphate or collagen/epinephrine surface under high-shear conditions. The time required for full occlusion of the aperture by the platelet plug is designated as the closure time . PFA-100 measurements do not correlate with platelet counts in healthy parturients, but they may demonstrate impairment in platelet function with severe preeclampsia.
THROMBOCYTOPENIC COAGULOPATHIES
Thrombocytopenia is defined as a platelet count < 150,000/µL. It affects 5% to 10% of the pregnant population, becoming more frequent as pregnancy advances. Gestational thrombocytopenia (also known as essential thrombocytopenia) is the most common cause of thrombocytopenia in the second half of pregnancy ( Table 44.5 ). Platelet count rarely decreases below 80,000/µL, and no changes in clinical management are indicated. When platelet count decreases below 100,000/µL, pathologic thrombocytopenic conditions should be considered, including: (1) primary immune thrombocytopenic purpura (ITP) (2) preeclampsia or hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome; (3) DIC; (4) thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome; (5) acute fatty liver of pregnancy (AFLP); (6) secondary immune thrombocytopenia (e.g., drug-induced thrombocytopenia, antiphospholipid syndrome, systemic lupus erythematosus, viral infection); (7) posttransfusion purpura (in individuals who have received a blood transfusion in the previous 1 to 2 weeks) and (8) inherited platelet disorders (e.g., Bernard-Soulier syndrome). Pseudothrombocytopenia is a laboratory artifact in which chelation of calcium ions by ethylene-diamine-tetraacetic acid exposes antigenic sites that react with antibodies, causing clumping that artificially lowers the platelet count. In these cases, the automated platelet count is normal if citrate anticoagulant is used.
Table 44.5
Leading Thrombocytopenia Diagnoses Based on Trimester of Presentation and Platelet Count
Adapted from Cines DB, Levine LD. Thrombocytopenia in pregnancy. Blood . 2017;130:2271–2277.
| First Trimester | Second Trimester | Second Trimester | Third Trimester | Third Trimester | |
|---|---|---|---|---|---|
| Platelet count (per µL) | >100,000 | <100,000 | >100,000 | <50,000 | |
| Diagnosis | ATP | GT | ATP | GT | Preeclampsia |
| HT | Preeclampsia | Preeclampsia | Preeclampsia | ATP | |
| Other | ATP | IPD | Other | Other | |
| TTP | Other | Other | ATP | TTP | |
| IPD | GT | IPD | IPD | ||
| TTP | TTP | TTP | GT |
Diagnoses are listed from most common to least common within each category. ATP , Autoimmune thrombocytopenic purpura; GT, gestational thrombocytopenia; HT , hereditary thrombocytopenia; IPD, inherited platelet disorders; TTP, thrombotic thrombocytopenic purpura.
Immune Thrombocytopenic Purpura
Although ITP (also called autoimmune thrombocytopenic purpura and idiopathic thrombocytopenic purpura) is rare, with an incidence of between 0.01% and 0.03%, it composes the majority of cases of thrombocytopenia in the first and second trimesters of pregnancy, and a sizable percentage of cases with maternal platelet counts below 80,000/µL throughout pregnancy (see Table 44.5 ). In this condition, immunoglobin G (IgG) antibodies directed against platelet antigens are produced in the spleen, liver, and bone marrow, resulting in impaired platelet production and accelerated destruction.
Interaction With Pregnancy
Conservative management is typically sufficient for ITP during pregnancy. Symptoms (e.g., gingival bleeding, hematuria, gastrointestinal bleeding) suggest profound thrombocytopenia ; corticosteroids are indicated if the platelet count is less than 30,000/µL before the onset of labor or if the patient requires a procedure during pregnancy (e.g., amniocentesis, surgery).
Therapy is frequently indicated in preparation for delivery, both to achieve minimum platelet count thresholds for safe cesarean delivery (>50,000/µL) and epidural catheter placement (generally greater than 70,000/µL), and to reduce risk for postpartum hemorrhage, which appears to correlate with the degree of platelet deficit.
Prednisone 10 to 20 mg per day is the initial treatment for ITP, with titration over 2 to 4 weeks to the minimum dose that achieves an adequate platelet count for delivery. Unlike dexamethasone, prednisone is almost completely inactivated by the placenta, with minimal transfer to the fetus. If there is insufficient time to titrate prednisone, or there is no response to corticosteroid therapy, intravenous immune globulin produces a rapid but transient increase in the platelet count. High-dose treatment (1000 mg/kg per day for 1 to 2 days) can achieve platelet count goals within 7 days.
In some women with preexisting ITP who become pregnant, thrombocytopenia becomes sufficiently severe that administration of high-dose corticosteroids and immune globulin is inadequate. Splenectomy is a second-line treatment and can be accomplished safely during the second trimester of pregnancy; women who have undergone splenectomy are at increased risk for infection with encapsulated organisms. Thrombopoietin-receptor agonists (e.g., romiplostim) are used in nonpregnant patients with ITP and are increasingly described in case reports and case series of pregnant women, particularly in the third trimester to prepare for delivery. The drugs cross the placenta and into breastmilk; documented complications include maternal venous thrombosis and neonatal thrombocytosis. Rituximab, dapsone, azathioprine, and cyclosporine are alternative options that have been used in nonpregnant patients who have side effects with other therapies, but evidence for safe use in pregnancy is lacking.
Platelet transfusions should be reserved to treat life-threatening hemorrhage or to prepare a patient for urgent surgery, as large doses of platelets may not achieve therapeutic goals and any increase will be transient. Standard postpartum uterotonic therapies achieve uterine contraction and minimize risk of hemorrhage related to atony. Tranexamic acid can be considered after delivery. In the days after delivery, the platelet count often returns to normal in these patients.
Obstetric Management
Although maternal IgG can cross the placenta and cause fetal thrombocytopenia, severe perinatal hemorrhagic complications are rare. Although there is a correlation between maternal platelet-associated IgG and fetal thrombocytopenia, it is not possible to predict the degree of fetal thrombocytopenia based on maternal platelet count or serology. Maternal ITP should not be confused with fetal-neonatal alloimmune thrombocytopenia , in which maternal antibodies specific to a fetal platelet antigen cause perinatal thrombocytopenia, increasing the risk for perinatal intracranial hemorrhage.
No study has demonstrated a correlation between the fetal platelet count and intrapartum fetal risk. Neonatal intracranial hemorrhage is rare, is not related to the method of delivery, and most commonly presents greater than 24 hours after delivery at the nadir of neonatal platelet count. Thus, current guidelines recommend that cesarean delivery should be reserved for obstetric indications. Forceps delivery, vacuum extraction, and episiotomies are frequently avoided, given the increased risk for bleeding.
Thrombotic Thrombocytopenic Purpura
The classic pentad that defines the syndrome of TTP includes (1) thrombocytopenia (platelet count as low as 10,000/µL); (2) microangiopathic hemolytic anemia; (3) fever; (4) neurologic signs such as photophobia, headache, and seizures; and (5) renal failure. Only the first two elements are essential for diagnosis. Disseminated platelet aggregation is a hallmark of TTP. Ischemic injury results from the deposition of platelet emboli and may lead to cerebral signs (headache, confusion, seizure, focal deficits, coma), renal signs (proteinuria, increased serum creatinine), splanchnic symptoms (nausea, vomiting, abdominal pain, diarrhea), or cardiac symptoms (chest pain, shortness of breath). Diseases that share some of the clinical findings of TTP include DIC, preeclampsia, HELLP syndrome, acute systemic vasculitis, and hemolytic-uremic syndrome.
TTP is associated with either a congenital or immune-mediated deficiency of the enzyme ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). ADAMTS13 is responsible for cleaving vWF multimers. These multimers promote systemic platelet aggregates and microemboli in cerebral, coronary, splenic, and renal microvasculature. The presence of vWF (but not fibrinogen) in platelet aggregates helps differentiate TTP from DIC (in DIC, fibrinogen but not vWF is found in platelet aggregates).
Pregnancy is a precipitating event for both initial and recurrent episodes of TTP, particularly among women with congenital ADAMTS13 deficiency, also known as Upshaw-Schulman syndrome. While vWF increases throughout pregnancy, ADAMTS13 activity decreases by 50% between the second trimester until delivery, and then recovers to prepregnancy values by 3 weeks postpartum. Consequently, acute TTP most often presents in the second half of pregnancy.
Prompt diagnosis and effective treatment for TTP appear to improve both maternal and fetal survival, although perinatal loss remains significant if the disease develops in the first and second trimesters. Diagnosis of TTP may be delayed because of a misdiagnosis with HELLP syndrome; concurrent diagnoses have been reported. Clinical signs that suggest TTP include microangiopathic anemia, platelet count < 30,000/µL, international normalized ratio < 1.3, MCV < 86.5 fL, creatinine < 2 g/dL, and a high ratio of lactate dehydrogenase to aspartate aminotransferase.
In the presence of concerning laboratory findings and life-threatening neurologic or cardiac signs, daily therapeutic plasma exchange (with an exchange volume of 1.0 to 1.5 times the predicted plasma volume of the patient) is recommended while awaiting the results of ADAMTS13 activity and anti-ADAMTS13 antibody levels. Once a diagnosis of immune-mediated TTP is confirmed, plasma exchange is continued until the platelet count recovers to 150,000/µL or greater. Adjuvant immunosuppressant therapy with corticosteroids (and possibly rituximab) may be needed to reduce antibodies to ADAMTS13. For congenital TTP, plasma exchange may be replaced by plasma infusions (10 to 15 mL/kg daily) until clinical remission, followed by maintenance infusions throughout pregnancy and puerperium.
For pregnant patients with a history of immune-mediated TTP, the International Society on Thrombosis and Haemostasis (ISTH) recommends prophylactic plasma exchange if ADAMTS13 levels decrease below 30 U/dL or 30% of normal. For congenital ADAMTS13 deficiency, ADAMTS13 surveillance and regular plasma infusions limit disease recrudescence. Human plasma–derived factor VIII concentrate contains variable concentrations of vWF, so plasma infusion is the preferred treatment for TTP in pregnancy. Coadministered low-dose aspirin may limit the risk of placental vasculopathy and comorbid preeclampsia.
Platelet transfusions may increase morbidity due to increased platelet clumping, but may be safe if administered immediately before or after plasma exchange therapy. Neuraxial anesthesia is not recommended in the setting of TTP with thrombocytopenia, but may be appropriate for patients with well-managed disease, as evidenced by a normal platelet count and lactate dehydrogenase (LDH) level. One case report described spinal anesthesia administered for cesarean delivery in a woman with familial ADAMTS13 deficiency treated with fresh frozen plasma.
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