Hematological Disorders
BS. Nguyễn Hồng Anh
Pregnant women are susceptible to several hematological
abnormalities that may aect any woman o childbearing
age. Tese include chronic disorders such as hereditary anemias, immunological thrombocytopenia, and hematological
malignancies. Other disorders arise rom pregnancy-induced
demands. wo are iron deciency and megaloblastic anemias.
Pregnancy may also unmask underlying hematological conditions. Importantly, pregnancy induces physiological changes
that oten conuse diagnosis and assessment o these disorders
(Chap. 4, p. 60).
ANEMIAS
■ Definition and Incidence
Normal values or concentrations o many cellular elements
during pregnancy are listed in the Appendix (p. 1227). Te
Centers or Disease Control and Prevention (1998) dened
anemia in iron-supplemented pregnant women using a cuto o the 5th percentile, which is 11 g/dL in the rst and
third trimesters and 10.5 g/dL in the second trimester. Notably, these were not based on a U.S. population. Table 59-1
describes the distribution o hematocrit values o 480 ironsucient women at Parkland Hospital (Zokie, 2020). Using
these data, values below 30 percent seem reasonable to dene
anemia.
Te modest all in hemoglobin and hematocrit values
during pregnancy stems rom a relatively greater expansion o plasma volume compared with red cell volume
(Georgie, 2020). Te disproportion between the rates at
which plasma and erythrocytes add to the maternal circulation is greatest during the second trimester. Late in pregnancy, plasma expansion essentially ceases, while hemoglobin
mass continues to accrue.
Te causes o more common anemias encountered in pregnancy are listed in Table 59-2. Teir requency is dependent on
IRON-DEFICIENCY ANEMIA. . . . . . . . . . . . . . . . . . . . . . 1049
MEGALOBLASTIC ANEMIA . . . . . . . . . . . . . . . . . . . . . . 1050
HEMOLYTIC ANEMIA. . . . . . . . . . . . . . . . . . . . . . . . . . . 1050
APLASTIC AND HYPOPLASTIC ANEMIA. . . . . . . . . . . . 1052
POLYCYTHEMIAS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1053
HEMOGLOBINOPATHIES. . . . . . . . . . . . . . . . . . . . . . . . 1053
THALASSEMIA SYNDROMES. . . . . . . . . . . . . . . . . . . . . 1056
PLATELET DISORDERS. . . . . . . . . . . . . . . . . . . . . . . . . . 1058
THROMBOTIC MICROANGIOPATHIES . . . . . . . . . . . . . 1060
INHERITED COAGULATION DEFECTS. . . . . . . . . . . . . . 1061
REFERENCES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
Pregnant women are susceptible to several hematological
abnormalities that may aect any woman o childbearing
age. Tese include chronic disorders such as hereditary anemias, immunological thrombocytopenia, and hematological
malignancies. Other disorders arise rom pregnancy-induced
demands. wo are iron deciency and megaloblastic anemias.
Pregnancy may also unmask underlying hematological conditions. Importantly, pregnancy induces physiological changes
that oten conuse diagnosis and assessment o these disorders
(Chap. 4, p. 60).
Hematological Disorders
CHAPTER 59
TABLE 59-1. Hematocrit Values in Pregnancy
Te causes o more common anemias encountered in pregnancy are listed in Table 59-2. Teir requency is dependent on
IRON-DEFICIENCY ANEMIA. . . . . . . . . . . . . . . . . . . . . . 1049
MEGALOBLASTIC ANEMIA . . . . . . . . . . . . . . . . . . . . . . 1050
HEMOLYTIC ANEMIA. . . . . . . . . . . . . . . . . . . . . . . . . . . 1050
APLASTIC AND HYPOPLASTIC ANEMIA. . . . . . . . . . . . 1052
POLYCYTHEMIAS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1053
HEMOGLOBINOPATHIES. . . . . . . . . . . . . . . . . . . . . . . . 1053
THALASSEMIA SYNDROMES. . . . . . . . . . . . . . . . . . . . . 1056
PLATELET DISORDERS. . . . . . . . . . . . . . . . . . . . . . . . . . 1058
THROMBOTIC MICROANGIOPATHIES . . . . . . . . . . . . . 1060
INHERITED COAGULATION DEFECTS. . . . . . . . . . . . . . 1061
REFERENCES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
Pregnant women are susceptible to several hematological
abnormalities that may aect any woman o childbearing
age. Tese include chronic disorders such as hereditary anemias, immunological thrombocytopenia, and hematological
malignancies. Other disorders arise rom pregnancy-induced
demands. wo are iron deciency and megaloblastic anemias.
Pregnancy may also unmask underlying hematological conditions. Importantly, pregnancy induces physiological changes
that oten conuse diagnosis and assessment o these disorders
(Chap. 4, p. 60).
Hematological Disorders
CHAPTER 59
TABLE 59-1. Hematocrit Values in Pregnancy
Percent
5th
percentile
50th
percentile
75th
percentile
1st trimester 33.0 37.5 41.2
2nd trimester 30.5 35.7 39.2
Predelivery 30.7 36.5 40.5Hematological Disorders 1049
ChApTEr 59
■ Iondeficiency Anemia
Te two most common causes o anemia during pregnancy
and the puerperium are iron deciency and acute blood loss
(Vandevijvere, 2013). In a typical singleton gestation, the
maternal need or iron averages nearly 1000 mg (Chap. 4,
p. 60). Multietal gestational requirements are considerably
higher (Ru, 2016). Tese amounts exceed the iron stores o
most women and result in iron-deciency anemia unless supplementation is provided.
In the third trimester, additional iron is needed to augment
maternal hemoglobin levels and or transport to the etus.
Because the amount o iron diverted to the etus is similar in
a normal and in an iron-decient mother, the newborn o a
severely anemic mother does not suer rom iron-deciency
anemia. Neonatal iron stores are related to maternal iron status
and to timing o cord clamping.
Iron deciency oten maniests as an appreciable drop in
hemoglobin concentration. Classic morphological evidence is
erythrocyte hypochromia and microcytosis (Fig. 59-1). Tese
may be less prominent in the pregnant woman. A mean corpuscular volume <80 L is classically seen (Appendix, p. 1227)
(James, 2021). Serum erritin levels normally decline during
pregnancy, and levels below 10 to 15 mg/L conrm irondeciency anemia. In addition, hepcidin levels drop in pregnancy. Tis hormone inhibits iron transport by binding to the
iron-export channel erroportin.
Routinely in pregnancy, daily oral supplementation with 30 to
60 mg o elemental iron and 400 μg o olic acid is recommended
(World Health Organization, 2016). For iron-deciency anemia,
resolution and restitution o iron stores can be accomplished
with simple iron salts that provide approximately 200 mg daily
o elemental iron. Tese include errous sulate, umarate, or
gluconate. I a woman cannot take oral iron preparations, parenteral therapy is given. Although both are administered intravenously, errous sucrose is saer than iron dextran (Auerbach,
2020; Pavord, 2020).
Moderate iron-deciency anemia responds to adequate
iron therapy, and the hematological response is an elevated
multiple actors such as geography, ethnicity, socioeconomic
level, nutrition, preexisting iron status, and prenatal iron supplementation (American College o Obstetricians and Gynecologists, 2021). In the United States, the prevalence o anemia
in pregnancy is 3 to 38 percent (Centers or Disease Control
and Prevention, 1989).
Initial evaluation o a pregnant woman with moderate anemia includes measurements o hemoglobin, hematocrit, red cell
indices, and serum iron or erritin levels; careul examination
o a peripheral blood smear; and a sickle-cell preparation i the
woman has Arican lineage (Appendix p. 1227).
■ Effects on pegnancy Outcomes
Anemia is associated with several adverse pregnancy outcomes (American College o Obstetricians and Gynecologists,
2021; Rahmati, 2020). Most anemia studies during pregnancy describe large populations and nutritional anemias. In
a Canadian study, 12 percent o more than 500,000 women
had mild anemia dened by a hemoglobin concentration o
9.0 to 10.9 g/dL (Smith, 2019). Tese women had a 2.5-
old increased risk or blood transusions. With moderate
anemia, incidences o etal-growth restriction, low 5-minute Apgar score, and perinatal mortality were increased. Ray
and coworkers (2020) reported similar results. Correction o
iron-deciency anemia results in a lower transusion rate with
delivery (Ibinosa, 2020).
A seemingly paradoxical nding is that healthy pregnant
women with higher hemoglobin concentrations also are at
greater risk or adverse perinatal outcomes (von empelho,
2008). Tis may result rom lower than average plasma volume
expansion o pregnancy concurrent with normal red cell mass
accrual. Scanlon and associates (2000) studied the relationship
between maternal hemoglobin levels and rates o preterm or
growth-restricted newborns. Women whose hemoglobin concentration was three standard deviations above the mean at 12
or 18 weeks’ gestation had a 1.3- to 1.8-old greater incidence
o etal-growth restriction. Placental weight correlates negatively with maternal hemoglobin concentration (Larsen, 2016).
Tese ndings have led some to the illogical conclusion that
withholding iron to cause iron-deciency anemia will improve
pregnancy outcomes (Ziaei, 2007).
TABLE 59-2. Causes of Anemia During Pregnancy
Acquired
Iron-deficiency anemia
Acute blood-loss anemia
Anemia of chronic disease
Megaloblastic anemia
Hemolytic anemias
Aplastic or hypoplastic anemia
Hereditary
Thalassemias
Sickle-cell hemoglobinopathies
Other hemoglobinopathies
Hemolytic anemias
FIGUrE 59-1 In this peripheral blood smear, iron-deficiency anemia is reflected by scattered microcytic and hypochromic red cells
(arrows). (Reproduced with permission from Dr. Siayareh Rambally.)1050
Section 12
Medical and Surgical Complications
reticulocyte count. In gravidas, the rise o hemoglobin concentration or hematocrit is typically slower than in nonpregnant women due to the larger plasma volumes o pregnancy.
Hemoglobin and erritin levels show equivalent rises in women
treated with either oral or parenteral iron therapy (Breymann,
2017; Daru, 2016; Neogi, 2019).
■ Anemia fom Acute Blood Loss
In early pregnancy, anemia caused by acute blood loss is common
with abortion, ectopic pregnancy, and hydatidiorm mole. Postpartum, anemia commonly stems rom obstetrical hemorrhage. Massive hemorrhage demands immediate treatment and is described
in Chapter 44 (p. 771). I a moderately anemic woman—dened
by a hemoglobin value o approximately 7 g/dL—is hemodynamically stable, is able to ambulate without adverse symptoms, and is
not septic, then blood transusions are not indicated. Instead, oral
iron therapy is provided or at least 3 months.
■ Anemia of Conic Disease
Diseases associated with chronic infammation can cause mild to
moderate anemia. Anemia stems rom several cytokines produced
by infammatory cells. Tese restrict erythropoiesis and shorten
red cell liespan. Hepcidin levels are elevated with chronic infammation, and this inhibits iron-exporting activity rom enterocytes
(Ross, 2017). Anemia is usually characterized by slightly hypochromic and microcytic erythrocytes, low transerrin saturation,
and a high serum erritin level (Ganz, 2019). Along with iron
deciency, it is the most common orm o anemia worldwide.
During pregnancy, women with chronic disorders may
develop anemia or the rst time. In those with preexisting
anemia, it may worsen as plasma volume expands. Frequent
causes include chronic renal insuciency, infammatory bowel
disease, and connective tissue disorders. Others are granulomatous inections and malignant neoplasms.
Chronic renal insuciency is the most common disorder
that we have encountered during pregnancy as a cause o this
anemia type. Some cases are accompanied by erythropoietin
deciency. During pregnancy in women with mild chronic
renal disease, the degree o red cell mass expansion is inversely
related to renal impairment (Chap. 56, p. 1004). At the same
time, plasma volume expansion usually is normal, and thus
anemia severity intensies (Cunningham, 1990).
For treatment, adequate iron stores must be ensured. Recombinant erythropoietin, with or without intravenous iron, has been
used to treat anemia stemming rom chronic disease (Ganz,
2019). In pregnancies complicated by chronic renal insu-
ciency, recombinant erythropoietin is usually considered when
the hematocrit approximates 20 percent (Cyganek, 2011). One
side eect is hypertension, which is already prevalent in women
with renal disease. Red cell aplasia and antierythropoietin antibodies also have been reported (McCoy, 2008).
■ Megaloblastic Anemia
Folic Acid Deficiency
Megaloblastic anemias are characterized by blood and bone
marrow abnormalities rom impaired DNA synthesis. Tis
leads to large cells with arrested nuclear maturation, whereas
the cytoplasm matures more normally. Worldwide, the pregnancy prevalence o this anemia varies considerably but is low
in the United States.
Megaloblastic anemia developing during pregnancy almost
always results rom olic acid deciency. In the past, this condition was called pernicious anemia o pregnancy. It usually is ound
in women who do not consume resh green leay vegetables,
legumes, or animal protein. As olate deciency and anemia
worsen, anorexia oten intensies and urther aggravates the
dietary deciency. Other causes are malabsorption syndromes
that include tropical sprue, extensive jejunal resection, gastrectomy, and Crohn disease; hemolytic anemias; malignancy; and
some antiolate drugs (Hobrand, 2018).
Nonpregnant women need 50 to 100 μg o olic acid daily.
During pregnancy, requirements rise, and 400 μg/d is recommended. Te earliest biochemical evidence is low plasma olic
acid concentrations (Appendix, p. 1227). Early morphological changes usually include hypersegmented neutrophils and
macrocytic erythrocytes. As the anemia worsens, peripheral
nucleated erythrocytes appear, and bone marrow examination discloses megaloblastic erythropoiesis. Anemia may then
become severe, and thrombocytopenia, leukopenia, or both
may develop. Te etus and placenta eectively extract olate
rom maternal circulation, and the etus is not anemic despite
severe maternal anemia.
For treatment, 5 to 15 mg o oral olic acid is provided with
iron, and a nutritious diet is encouraged (Hobrand, 2018). At
4 to 7 days o treatment, the reticulocyte count is higher, and
leukopenia and thrombocytopenia are corrected.
For anemia prevention, a diet should contain sucient olic
acid. Moreover, the role o olate deciency in the genesis o
neural-tube deects is well studied (Chap. 15, p. 276).
Vitamin B12 Deficiency
With pregnancy, vitamin B12 levels are lower than nonpregnant
values because levels o binding proteins, namely, the transcobalamins decline. However, in most gravidas, megaloblastic
anemia is rarely rom vitamin B12 deciency. O predisposing
conditions, vitamin B12 deciency in pregnancy is more likely
encountered ollowing gastric resection. Women who have
undergone total gastrectomy require 1000 μg o intramuscular
vitamin B12 (cyanocobalamin) monthly. Tose with a partial
gastrectomy usually do not need supplementation, but adequate serum vitamin B12 levels should be ensured (Appendix,
p. 1230). Other causes o megaloblastic anemia rom vitamin
B12 deciency include Crohn disease, ileal resection, some drugs,
and bacterial overgrowth in the small bowel (Hobrand, 2018).
Addisonian pernicious anemia results rom absent intrinsic actor that is requisite or dietary vitamin B12 absorption. Tis
autoimmune disorder usually has its onset ater age 40 years,
which accounts or its uncommon occurrence in pregnancy
(Govindappagari, 2019).
■ hemolytic Anemia
Several conditions accelerate erythrocyte destruction. Hemolysis may be a primary disorder, and sickle-cell disease andHematological Disorders 1051
ChApTEr 59
2001). We have cared or a woman who during each pregnancy
developed severe hemolysis with anemia that responded to
prednisone. Her etuses were not aected, and hemolysis abated
spontaneously ater delivery.
In some cases, hemolysis is induced by conditions unique
to pregnancy. Mild microangiopathic hemolysis with thrombocytopenia is relatively common with severe preeclampsia and
eclampsia (Cunningham, 2015; Kenny, 2015). Tis HELLP
(hemolysis, elevated liver enzyme levels, low platelet count)
syndrome is discussed in Chapter 40 (p. 699). Another example is acute atty liver o pregnancy, which causes moderate to
severe hemolytic anemia (Chap. 58, p. 1033).
Paroxysmal Nocturnal Hemoglobinuria
Although commonly regarded as a hemolytic anemia, this
hemopoietic stem cell disorder is characterized by ormation
o deective platelets, granulocytes, and erythrocytes. Paroxysmal nocturnal hemoglobinuria is acquired and arises rom one
abnormal clone o cells, much like a neoplasm. In contrast, one
mutated X-linked gene responsible or this condition is termed
PIG-A because it codes or phosphatidylinositol glycan protein
A. Resultant abnormal anchor proteins o the erythrocyte and
granulocyte membrane make these cells unusually susceptible
to lysis by complement. A serious complication is thrombosis,
which is heightened in the hypercoagulable state o pregnancy.
Chronic hemolysis has an insidious onset, and its severity ranges rom mild to lethal. Hemoglobinuria develops at
irregular intervals and is not necessarily nocturnal. Hemolysis
may be initiated by transusions, inections, or surgery. Almost
40 percent o patients suer venous thromboembolism (VE)
and may also experience renal ailure, hypertension, and BuddChiari syndrome. o counter the VE risk, prophylactic anticoagulation is recommended (Luzzato, 2018). Te preerred
treatment is eculizumab (Soliris), an antibody that inhibits
complement activation (Kelly, 2015; Steanovic, 2019). Te
drug is apparently sae in pregnancy (Sarno, 2019). Median
survival ater diagnosis o the syndrome is 10 years, and bone
marrow transplantation is the denitive treatment.
During pregnancy, paroxysmal nocturnal hemoglobinuria
can be serious and unpredictable. Complications may aect up
to three ourths o aected women, and the maternal mortality
rate in the past was 10 to 20 percent (de Guibert, 2011). Complications more oten develop postpartum, and hal o aected
women develop VE. Kelly and coworkers (2015) described
75 pregnancies in 61 aected women treated with eculizumab.
Tey described no maternal deaths, but the stillbirth rate was
4 percent. Miyasaka and associates (2016) ound similar results.
Bacterial Toxins
Te most ulminant acquired hemolytic anemia encountered
during pregnancy is caused by the exotoxin o Clostridium per-
ringens or by group A β-hemolytic streptococcus (Chap. 50,
p. 890). In additional, endotoxin o gram-negative bacteria,
that is, lipopolysaccharide, may be accompanied by hemolysis and mild to moderate anemia (Cox, 1991). For example,
anemia oten accompanies acute pyelonephritis. With normal
erythropoietin production, red cell mass is restored ollowing
inection resolution (Cavenee, 1994; Dotters-Katz, 2013).
hereditary spherocytosis are examples. In others, hemolysis
complicates an underlying condition such as systemic lupus
erythematosus or preeclampsia. Microangiopathic hemolytic
anemia rom malignancy has been reported in pregnancy
(Happe, 2016).
Autoimmune Hemolysis
Te cause o aberrant antibody production is unknown. ypically, both the direct and indirect antiglobulin (Coombs) tests
are positive. Anemias caused by these actors may be due to
warm-active autoantibodies (80 to 90 percent), cold-active
antibodies, or a combination. Tese syndromes may also be
classied as primary (idiopathic) or secondary due to underlying diseases or other actors. Examples o the secondary group
include lymphomas and leukemias, connective tissue diseases,
inections, chronic infammatory diseases, and drug-induced
antibodies (Knuesel, 2018). Cold-agglutinin disease may be
induced by inectious etiologies such as Mycoplasma pneumoniae or Epstein-Barr viral mononucleosis. Hemolysis and
positive antiglobulin test results may be the consequence o
either immunoglobulin M (IgM) or immunoglobulin G (IgG)
antierythrocyte antibodies. When thrombocytopenia is comorbid, it is termed Evans syndrome (Wright, 2013).
In pregnancy, hemolysis can be markedly accelerated.
Low-dose rituximab (ruxima)—100mg weekly or 4 weeks—
coupled with prednisone, is rst-line treatment (Luzzatto,
2018). Coincidental thrombocytopenia usually corrects with
therapy. ransusion o red cells is complicated by antierythrocyte antibodies, but warming the donor cells to body temperature may decrease their destruction by cold agglutinins. In rare
cases, the etus may be involved (Maroto, 2020).
Drug-induced Hemolysis
Tese hemolytic anemias must be dierentiated rom other
causes o autoimmune hemolysis. In most cases, hemolysis is mild and resolves with drug withdrawal. Subsequently,
avoiding the drug is preventive. One mechanism is hemolysis induced through drug-mediated immunological injury to
red cells. I bound to a red cell protein, the drug may act as a
high-anity hapten to which antidrug antibodies attach. An
example is IgM antipenicillin or anticephalosporin antibodies.
Garratty and colleagues (1999) described seven women with
severe Coombs-positive hemolysis stimulated by ceotetan given
as prophylaxis or obstetrical procedures. Alpha-methyldopa
can cause similar hemolysis (Grigoriadis, 2013). Some other
drugs, which include probenecid, quinidine, and riampin, act
as low-anity haptens and adhere to cell membrane proteins.
A requent mechanism or drug-induced hemolysis relates to
a congenital erythrocyte enzymatic deect, such as glucose-
6-phosphate dehydrogenase deciency (p. 1052).
Pregnancy-associated Hemolysis
Unexplained severe hemolytic anemia can develop during
early pregnancy and resolves within months postpartum. Clear
immune mechanisms or red cell deects are not contributory.
Because the etus–neonate also may demonstrate transient
hemolysis, an immunological cause is suspected. Maternal corticosteroid treatment is oten—but not always—eective (Kumar,1052
Section 12
Medical and Surgical Complications
Inherited Erythrocyte Membrane Defects
Te normal erythrocyte is a fexible biconcave disc that allows
numerous cycles o reversible deormations. Several genes encode
erythrocyte structural membrane proteins and intraerythrocytic
enzymes. Various mutations can destabilize the lipid bilayer.
Te loss o lipids rom the cell membrane causes a surace area
deciency and poorly deormable erythrocytes that undergo
hemolysis (Iolascon, 2019). Anemia severity depends on the
degree o rigidity. Erythrocyte morphology similarly is dependent on these actors, and these disorders are usually named
ater the most dominant red cell shape. Tree examples are
hereditary spherocytosis, pyropoikilocytosis, and ovalocytosis.
Hemolytic anemias that compose this group o inherited
membrane deects are among the most common complicating
pregnancy. Mutations are usually an autosomally dominant,
variably penetrant α- and β-spectrin deciency. Others are
dominant or recessive gene mutations that result rom de-
ciency o ankyrin, band 3, 4.1, and 4.2, or combinations o
these (Luzzato, 2018; Rencic, 2017). Te degrees o anemia
and jaundice vary, and diagnosis is conrmed by identication o abnormal erythrocytes on peripheral smear and their
increased osmotic ragility.
Spherocytic anemias may be associated with a crisis typied
by severe anemia rom accelerated hemolysis, and it develops
in patients with an enlarged spleen. Inection can also accelerate hemolysis or suppress erythropoiesis to worsen anemia. An
example o the latter is parvovirus B19 inection (Chap. 67,
p. 1191). In severe cases, splenectomy reduces hemolysis, anemia, and jaundice.
In general, women with inherited erythrocyte membrane
deects do well during pregnancy. Oral olic acid supplementation o 4 mg daily is given to sustain erythropoiesis. Women
with hereditary spherocytosis cared or at Parkland Hospital
had hematocrits ranging rom 23 to 41 percent, with a mean
o 31 (Maberry, 1992). Reticulocyte counts varied rom 1 to
23 percent. Among 50 pregnancies in 23 women, eight women
miscarried. Four o 42 inants were born preterm, but none was
growth restricted. Inection in our women intensied hemolysis, and three o these required transusions. Similar results were
reported by Pajor and colleagues (1993).
Because these disorders are inherited, the newborn may be
aected. Preconceptional counseling emphasizes olic acid supplementation and provides an opportunity to discuss prenatal
diagnosis. Celkan and Alhaj (2008) report prenatal diagnosis
via cordocentesis at 18 weeks’ gestation and testing or osmotic
ragility. Although etal anemia is uncommon, newborns with
hereditary spherocytosis may maniest hyperbilirubinemia and
anemia shortly ater birth.
Erythrocyte Enzyme Deficiencies
An intraerythrocytic deciency o enzymes that permit anaerobic glucose metabolism may cause hereditary nonspherocytic
anemia. Most o these mutations are autosomal recessive traits.
Most episodes o severe anemia with these enzyme deciencies
are induced by drugs or inections.
Pyruvate kinase deciency has a requency o 1:10,000 persons and is associated with variable degrees o anemia (Luzzatto,
2018). Recurrent transusions in homozygous carriers can lead
to iron overload, and associated myocardial dysunction should
be monitored (Dolan, 2002). Te etus that is homozygous
or this mutation may develop hydrops etalis rom anemia and
heart ailure (Chap. 18, p. 360).
Glucose-6-phosphate dehydrogenase (G6PD) deciency is
complex because there are more than 200 enzyme variants.
Te most common stem rom a base substitution that leads to
an amino acid replacement and a broad range o phenotypic
severity (Luzzatto, 2018; Puig, 2013). In the homozygous or A
variant, both X chromosomes are aected, and erythrocytes are
markedly decient in G6PD activity. Approximately 2 percent
o Arican-American women are aected, and the heterozygous
variant is ound in 10 to 15 percent. In both cases, random
X-chromosome inactivation—lyonization—results in variable
enzyme activity.
During pregnancy, hemolysis severity in G6PD-decient
heterozygotes or homozygotes is related to enzyme activity.
Anemia is usually episodic, but some variants induce chronic
nonspherocytic hemolysis. Because young erythrocytes contain
more enzyme activity, anemia stabilizes and corrects soon ater
the inciting cause is resolved.
Tese women are oered preconceptional counseling to discuss risks o adverse pregnancy outcomes, precipitating actors
o hemolysis such as pyelonephritis and pneumonia, and the
limited list o sae medications available or treatment during
pregnancy. For example, macrodantin is used or pyelonephritis suppression in pregnancy but can induce hemolysis in those
with G6PD deciency. Because etal and neonatal maniestations are possible, these patients should undergo genetic counseling, with possible partner testing, to assess etal transmission
risk.
■ Alastic and hyolastic Anemia
Aplastic anemia is a grave complication characterized by pancytopenia and markedly hypocellular bone marrow (Young,
2018). Te unctional deect is a marked decline in the number o committed marrow stem cells. Etiologies are multiple,
and the inciting cause can be identied in approximately a
third o cases. Tese include immunological disorders, drugs,
other chemicals, inection, irradiation, leukemia, and inherited
conditions such as Fanconi anemia and Diamond-Blackan syndrome (Green, 2009).
Immunosuppressive therapy is given, and in some nonresponders, eltrombopag (Promacta) is successul (ownsley,
2017; Young, 2018). Denitive treatment is bone marrow
transplantation, and approximately three ourths o patients
have a good response and long-term survival (ichelli, 2020).
Umbilical cord blood–derived stem cells also can serve as a
potential transplant source (Moise, 2005; Pinto, 2008).
Pregnancy
Hypoplastic or aplastic anemia complicating pregnancy is rare.
A study o 60 pregnancies complicated by aplastic anemia
ound that hal were diagnosed during pregnancy (Bo, 2016).
In another series o 19 pregnancies, the complication rate was
79 percent, but no women died (McGowan, 2019). PregnancyHematological Disorders 1053
ChApTEr 59
induced hypoplastic anemia is rare, and the anemia and other
cytopenias improve or remit ollowing delivery or pregnancy
termination (Choudhry, 2002; Edahiro, 2020). In some cases,
anemia recurs in a subsequent pregnancy.
Diamond-Blackan anemia is rare orm o pure red cell hypoplasia. Approximately 40 percent o cases are amilial and have
autosomal dominant inheritance (Orali, 2004). Te response
to glucocorticoid therapy is usually good. Continuous treatment is necessary, and most become at least partially transusion dependent (Gansner, 2017). In a study o 64 pregnancies
complicated by this syndrome, two thirds had problems related
to placental vascular etiologies that included miscarriage, preeclampsia, preterm birth, etal-growth restriction, or stillbirth
(Faivre, 2006).
Gaucher disease is an autosomally recessive lysosomal
enzyme deciency characterized by decient activity o acid β-
glucosidase. Aected women have anemia and thrombocytopenia that usually worsens in pregnancy. Elstein and colleagues
(1997) described six pregnant women whose disease improved
with alglucerase enzyme replacement. Imiglucerase (Cerezyme)
is human recombinant enzyme replacement therapy.
Te major risks with hypoplastic anemia are hemorrhage and
inection. Rates o preterm labor, preeclampsia, etal-growth
restriction, and stillbirth are increased (Bo, 2016). Management depends on gestational age, and supportive care includes
continuous inection surveillance and prompt antimicrobial
therapy. Granulocyte transusions are given only during inections. Red cells are transused to improve symptomatic anemia
and routinely to maintain the hematocrit above 20 volumes
percent. Platelet transusions may be needed to control hemorrhage. Mortality rates reported since 1960 have averaged nearly
50 percent but have declined more recently (Giri, 2017).
Bone Marrow Transplantation
Several reports describe successul pregnancies in women who
have undergone bone marrow transplantation. In their review,
Sanders and coworkers (1996) reported 72 pregnancies in 41
such women. In the 52 pregnancies resulting in a liveborn
neonate, almost hal were complicated by preterm delivery or
hypertension. Data rom the National Cancer Institute regarding 102 pregnancies ollowing transplantation showed 71 liveborns, o which 16 were preterm. O all women, 20 percent
had decreased hemopoiesis, and transusions were required
(Giri, 2017). Carter and associates (2006) reported decreased
ertility but generally good pregnancy outcomes. Our experiences with a ew o these women indicate that they have normal
pregnancy-augmented erythropoiesis and total blood volume
expansion. In pregnancy, cell-ree DNA study results must
account or donor DNA contributions (Duque-Aonso, 2018).
pOLYCYThEMIAS
Excessive erythrocytosis during pregnancy is usually secondary and related to chronic hypoxia. Etiologies include maternal congenital cyanotic cardiac disease or a chronic pulmonary
disorder. In addition, we have encountered otherwise healthy
pregnant women who were heavy smokers, had chronic bronchitis, and had hematocrits ranging rom 55 to 60 volumes
percent! I polycythemia is severe, the probability o a successul
pregnancy outcome is low.
Polycythemia vera is a primary clonal myeloprolierative
hemopoietic stem cell disorder characterized by excessive prolieration o erythroid, myeloid, and megakaryocytic precursors. Virtually all patients have a JAK2 gene mutation (Spivak,
2018). Symptoms are related to greater blood viscosity, and
thrombotic complications are common. reatment o nonpregnant patients is with hydroxyurea or ruxolitinib.
Fetal loss rates are high in women with polycythemia vera,
and pregnancy outcome may be improved with aspirin therapy
(Bertozzi, 2018; Dewarrat, 2020). Women with a history o
VE are given prophylaxis with low-molecular-weight heparin
(Stein, 2019). I cytoreduction is required during pregnancy,
intereron alpha may be considered (Kreher, 2014).
hEMOGLOBINOpAThIES
■ Sicklecell hemoglobinoaties
Pathophysiology
Hemoglobin A is the most common hemoglobin tetramer and
consists o two α- and two β-globin chains. Genes HBA1 and
HBA2 each code or α-globin, whereas only HBB codes or
β-globin. Sickle hemoglobin (hemoglobin S) originates rom a
single β-globin substitution o glutamic acid by valine, which
stems rom an A-or- substitution. Hemoglobin C originates
rom a single β-globin substitution o glutamic acid by lysine,
which stems rom a -or-C substitution. Hemoglobinopathies
that can result in clinical eatures o the sickle-cell syndrome
include sickle-cell anemia (Hb SS); sickle-cell hemoglobin C
disease (Hb SC); sickle-cell β-thalassemia disease (either Hb
S/B0 or Hb S/B+); and sickle-cell E disease (Hb SE). All are
associated with higher pregnancy morbidity.
When deoxygenated, red cells containing hemoglobin S
undergo sickling, and the hemoglobin aggregates (Fig. 59-2).
Constant sickling and unsickling damages the cell membrane,
and its shape may become irreversibly sickled. Events that slow
FIGUrE 59-2 Peripheral smear of sickle cells (arrows) characteristic of sickle-cell anemia. (Reproduced with permission from
Dr. Imran Hitto.)1054
Section 12
Medical and Surgical Complications
erythrocyte transit through the microcirculation include adhesion to endothelial cells, erythrocyte dehydration, and vasomotor dysregulation.
Clinically, sickling episodes are marked by ischemia and
inarction in various organs. Te sickle-cell crisis produces pain,
which is oten severe. Aplastic, megaloblastic, sequestration,
and hemolytic crises can develop.
Chronic and acute changes rom sickling include bony abnormalities such as osteonecrosis o emoral and humeral heads,
renal medullary damage, autosplenectomy in homozygous SS
patients but splenomegaly in other variants, hepatomegaly,
ventricular hypertrophy, pulmonary inarctions, cerebrovascular accidents, leg ulcers, and a propensity or inection and
sepsis (Benz, 2018; Ware, 2017). Pulmonary hypertension can
develop and is ound in 20 percent o adults with SS hemoglobin (Gladwin, 2008). Other sequelae are cerebrovascular aneurysms and sickle-cell vasculopathy (Buonanno, 2016).
Treatment
Good supportive care is essential to prevent mortality. Specic
therapies are evolving, and many are still experimental. One
treatment is hemoglobin F induction with drugs that stimulate
γ-globin synthesis. Remember that hemoglobin F is prominent
in etal lie (Chap. 7, p. 129). Tis induction raises hemoglobin F levels, which inhibits hemoglobin S polymerization. One
agent is hydroxyurea, which augments hemoglobin F production and reduces the number o sickling episodes (shilolo,
2019). Hydroxyurea is teratogenic in animals. A preliminary
17-year surveillance o antenatally exposed children was reassuring (Ballas, 2009; Briggs, 2017).
Other agents include biologic antibody drugs and l-glutamine (Ataga, 2017, Niihara, 2018; Steanovic, 2019). Various orms o hemopoietic cell transplantation are emerging as
“cures” or sickle-cell syndromes and severe thalassemias (Oringanje, 2013; Kanter, 2021). Last, gene therapy has been accomplished by viral vector–mediated addition o a β-globin gene
into stem cells (Harrison, 2019; Ribeil, 2017).
■ Sicklecell Syndomes Duing pegnancy
Pregnancy is a serious burden to women with any major sickle
hemoglobinopathy, particularly those with hemoglobin SS
(Table 59-3) (Kuo, 2016; Villers, 2008). Maternal mortality
rates have improved, but perinatal morbidity and mortality
rates remain ormidable (Bae, 2021; Oteng-Ntim, 2015). Tus,
women with sickle-cell hemoglobinopathies require close prenatal observation. Specically, any actor that impairs erythropoiesis or increases red cell destruction aggravates the anemia.
Prenatal olic acid supplementation with 4 mg daily is needed
to support rapid red blood cell turnover.
One danger is that a symptomatic woman may categorically
be considered to be suering rom a sickle-cell crisis. As a result,
serious obstetrical or medical problems that cause pain, anemia,
or both may be overlooked. Examples are ectopic pregnancy,
placental abruption, pyelonephritis, or appendicitis. Tus, a
diagnosis o sickle-cell crisis should be applied only ater all
other possible causes have been excluded. Pain with sickle-cell
syndromes is caused by intense sequestration o sickled erythrocytes and inarction in various organs, particularly bone
marrow. Tese episodes develop acutely, especially late in pregnancy, during labor and delivery, and early in the puerperium.
No randomized trials have evaluated treatment during pregnancy. At minimum, intravenous fuids are given, and opioids
are administered promptly or severe pain. Oxygen via nasal
cannula may decrease the sickling intensity at the capillary
level. We have ound that red cell transusions ater the onset
o severe pain do not dramatically relieve pain intensity and
may not shorten its duration. Conversely, as discussed later,
prophylactic transusions almost always prevent urther vasoocclusive episodes and pain crises. Antenatal epidural analgesia
may oer benets or pain (Verstraete, 2012; Winder, 2011).
Long term, aected women can become habituated to narcotics. Tis problem is highlighted by the elevated rates o neonatal abstinence syndrome, which is a constellation o withdrawal
symptoms (Shirel, 2016).
Rates o covert bacteriuria and acute pyelonephritis are
elevated substantively, and screening and treatment or bacteriuria are essential. I pyelonephritis develops, sickle cells are
extremely susceptible to bacterial endotoxin, which can incite
dramatic, rapid red cell destruction and suppress erythropoiesis. Pneumonia, especially due to Streptococcus pneumoniae,
is common. Te Centers or Disease Control and Prevention
(2020) recommends specic vaccination or those with sicklecell disease and all asplenic patients. Tese are polyvalent pneumococcal, Haemophilus infuenzae type B, and meningococcal
vaccines (able 10-7, p. 190).
Pulmonary complications are requent. O these, acute chest
syndrome is characterized by pleuritic chest pain, ever, cough,
lung inltrates, hypoxia, and usually bone and joint pain
(Vichinsky, 2000). It develops in approximately 6 percent o
pregnant women (Inparaj, 2020). In addition to symptoms,
radiographs show a new pulmonary inltrate. Te our precipitants are inection, marrow emboli, thromboembolism, and
atelectasis (Medo, 2005). Bacterial or viral inection causes
approximately hal o cases. When acute chest syndrome develops, the mean duration o hospitalization is 10.5 days. Mechanical ventilation is required in approximately 15 percent, and the
mortality rate nears 3 percent (Gladwin, 2008).
For nonpregnant adults, some recommend rapid simple
transusion or exchange transusions to remove the “trigger”
or acute chest syndromes (Ramphul, 2020). In a study o nonpregnant patients, urner and colleagues (2009) reported that
TABLE 59-3. Pregnancy Morbidity with Hemoglobin SS
and SC Disease
Odds Ratios
Outcome Hb SS Hb SC
Preeclampsia 2–3.1 2.0
Stillbirth 6.5 3.2
Preterm delivery 2–2.7 1.5
Growth restriction 2.8–3.9 1.5
Maternal mortality 11–23 11
From Boafor, 2016; Oteng-Ntim, 2015.Hematological Disorders 1055
ChApTEr 59
exchange transusion oered no increased benets compared
with simple transusions, and the ormer were associated with
ourold greater blood usage. Tese results notwithstanding, the
American Society o Hematology suggests exchange transusions
instead o simple transusions. However, they state this recommendation is conditional due to scarce high-quality evidence
(Chou, 2020).
Women with sickle-cell disease usually have some degree
o cardiac dysunction rom ventricular hypertrophy. Chronic
hypertension worsens the dysunction. During pregnancy, the
basal hemodynamic state characterized by high cardiac output and increased blood volume is augmented (Veille, 1994).
Although most women tolerate pregnancy without problems,
complications such as severe preeclampsia or serious inections
may result in ventricular ailure (Cunningham, 1986). Heart
ailure caused by pulmonary hypertension also must be considered.
In 4352 pregnancies in women with sickle-cell syndromes,
Chakravarty and associates (2008) reported signicantly higher
pregnancy complication rates. Compared with controls, women
with sickling disorders had a 63-percent rate o nondeliveryrelated admissions. Tey had a 1.8-old greater incidence o
hypertensive disorders—19 percent; a 2.9-old higher rate o
etal-growth restriction—6 percent; and a 1.7-old increased
cesarean delivery rate—45 percent.
With hemoglobin SC disease, morbidity and mortality
rates are appreciably lower than those rom sickle-cell anemia.
Indeed, ewer than hal o these women have symptoms beore
pregnancy. In our experiences, aected gravidas suer attacks
o severe bone pain and episodes o pulmonary inarction and
embolization more commonly than when not pregnant (Cunningham, 1983). Some adverse pregnancy outcomes are shown
in able 59-3.
Prophylactic Red Cell Transfusions
Chronic transusion therapy has the most dramatic benet on
maternal morbidity rates (Benites, 2016; Malinowski, 2015;
Vianello, 2018). It is problematic or universal application
because o complications rom multiple transusions. In an earlier 10-year prospective study at Parkland Hospital, we oered
prophylactic transusions to all pregnant women with sicklecell syndromes. ransusions were given throughout pregnancy
to maintain the hematocrit above 25 volumes percent and the
portion o hemoglobin S below 60 percent (Cunningham,
1979). Maternal morbidity was minimal, and erythropoiesis
suppression was not problematic. Teir outcomes were compared with historical controls who were not routinely trans-
used. Overall, maternal morbidity and hospitalization rates
were reduced in the transused group, but perinatal morbidity
and mortality rates remained increased because o preterm birth
and etal-growth restriction (Cunningham, 1983).
In a multicenter trial, Koshy and coworkers (1988) randomly
assigned 72 pregnant women with sickle-cell syndromes to prophylactic or indicated transusions. Tey reported a signicant
decline in the incidence o painul sickle-cell crises with prophylactic transusions but no dierences in perinatal outcomes.
Because o risks inherent with blood administration, they concluded that prophylactic transusions were not indicated.
A metaanalysis o 12 studies ound prophylactic transusions improved rates o most adverse maternal and neonatal
outcomes, including maternal mortality, pulmonary complications, and perinatal mortality (Malinowski, 2015). Undoubtedly, morbidity rom multiple transusions is signicant. Up
to 10 percent o women had a delayed hemolytic transusion
reaction, and inections are a major concern. Garratty (1997)
reviewed 12 studies and ound alloimmunization developed in
a ourth o women. Last, rom liver biopsies in these women,
we ound no evidence o transusion-related iron overload,
hemochromatosis, or chronic hepatitis (Yeomans, 1990).
Because o what some consider marginal benets, routine
prophylactic transusions during pregnancy remain controversial (American College o Obstetricians and Gynecologists,
2019b). Current consensus is that their use should be individualized. With such a practice, approximately 60 percent o
women will need transusions during pregnancy (Shari, 2018).
Fetal Assessment
Perinatal outcomes include increased risks or preterm birth,
etal-growth restriction, and perinatal mortality. Tus, beginning in the mid-second trimester, serial etal-growth assessment
with sonography is reasonable. At 32 to 34 weeks’ gestation,
weekly antepartum surveillance with biophysical proles or
nonstress test is considered (American College o Obstetricians and Gynecologists, 2019b). Anyaegbunam and colleagues
(1991) reported nonreactive stress tests during sickling crises,
which resumed reactivity with crisis resolution. Tey concluded
that transient eects o sickle-cell crisis do not compromise
umbilical blood fow. O interest, placentas rom sickle-cell
pregnancies show abnormalities in 69 percent (Malinowski,
2020).
Labor and Delivery
Management is essentially identical to that or women with cardiac disease (Chap. 52, p. 920). Women are kept comortable
but not oversedated. Conduction analgesia is ideal. Compatible blood should be available. I a dicult vaginal or cesarean
delivery is contemplated and the hematocrit is <20 volumes
percent, packed erythrocyte transusions are administered.
Vaginal delivery is suitable, and cesarean delivery is reserved
or obstetrical indications (Rogers, 2010).
In the puerperium, many clinicians do not recommend
combination hormonal contraception because o potential
adverse vascular and thrombotic eects. However, one systematic review ound that complication rates were not higher
with their use in women with sickle-cell syndromes (Haddad,
2012). Te Centers or Disease Control and Prevention categorizes combination hormonal contraception, intrauterine
devices, implants, and progestin-only methods as having no
risk or as having advantages that generally outweigh theoretical
or proven risks (Curtis, 2016).
■ Sicklecell Tait
Te requency o sickle-cell trait among Arican Americans
averages 8 percent. Carriers have occasional hematuria, renal
papillary necrosis, and hyposthenuria, which is urine o low1056
Section 12
Medical and Surgical Complications
C, and D or or β-thalassemia trait. Sickle-cell anemia results
rom the inheritance o the gene or S hemoglobin rom each
parent. In the United States, 1 o 12 Arican-Americans has
sickle-cell trait, which results rom inheritance o one gene
or hemoglobin S and one or normal hemoglobin A. Te
computed incidence o sickle-cell anemia among AricanAmericans is 1 in 576 (1/12 × 1/12 × 1/4 = 1/576). Te
disease is less common in adults because o earlier mortality.
Approximately 1 in 40 Arican-Americans has the gene or
hemoglobin C. Tus, the theoretical incidence or coinheritance o the gene or hemoglobin S and an allelic gene or
hemoglobin C in an Arican- American child is 1 in 2000
(1/12 × 1/40 × 1/4). β-Talassemia minor aects about 1
in 40, thus S-β-thalassemia also is ound in approximately 1
in 2000 (1/12 × 1/40 × 1/4).
Many tests are available to detect sickle-cell disease antenatally. Most are DNA based and use chorionic villus samples
or amnionic fuid specimens (American College o Obstetricians and Gynecologists, 2019b). Several mutations that
encode hemoglobin S and other abnormal hemoglobins can be
detected by targeted mutation analysis and polymerase chain
reaction–based techniques (Chap. 18, p. 325).
ThALASSEMIA SYNDrOMES
Hundreds o mutations aect the genes that control hemoglobin production (Benz, 2018). Some o these impair synthesis o
one or more o the normal globin peptides and may result in a
clinical syndrome characterized by varying degrees o ineective
erythropoiesis, hemolysis, and anemia. Talassemias are classi-
ed according to the globin that is decient. Te two major
orms involve impaired production or instability o α-globin
to cause α-thalassemia or o β-globin to cause β-thalassemia.
Clinically, these can be divided into transusion dependent and
nontransusion dependent (aher, 2018).
■ Ala Talassemias
Te two α-globin genes, HBA1 and HBA2, are both ound
on chromosome 16. Because diploid chromosome sets contains
our α-globin genes total, the inheritance o α-thalassemia is
more complicated than or β-thalassemia (Piel, 2014). Some
o the possible genotypes and phenotypes are shown in
Table 59-4. Te γ-globin genes are similarly duplicated. Correspondingly, the normal genotype or diploid cells can be
expressed as αα/αα and γγ/γγ. O the two main groups o
α-thalassemia determinants, α0-thalassemia is mutation o both
genes rom one chromosome (––/αα), whereas α+-thalassemia
is mutation o a single gene rom one allele (–α/αα heterozygote) or rom both alleles (–α/–α homozygote).
Te relative requency o the dierent α-thalassemia types
varies remarkably among racial groups, and all are encountered
in Asians. In those o Arican descent, although α-thalassemia
minor has a requency approximating 2 percent, hemoglobin H disease is rare and hemoglobin Bart disease is unreported. Tis is because Asians usually have α0-thalassemia
minor inherited with both gene deletions typically rom the
specic gravity (saras, 2009). Sickle trait may be associated
with progression o end-stage renal disease in blacks (Olaniran,
2020). Although controversial, sickle-cell trait does not appear
to be associated with increased rates o abortion, perinatal mortality, low birthweight, or pregnancy-induced hypertension
(Pritchard, 1973; Wellenstein, 2019; Wilson, 2020). In one
study o more than 5000 women, the incidence o gestational
hypertension was signicantly elevated, but that o preeclampsia was not (O’Hara, 2020). O note, they did not control or
chronic hypertension. One unquestioned relationship is the
twoold greater incidence o asymptomatic bacteriuria and urinary inection. Sickle-cell trait is not considered a deterrent to
pregnancy or to hormonal contraception.
■ hemoglobin C and CβTalassemia
Approximately 2 percent o Arican-Americans are heterozygous or hemoglobin C, but even i homozygous, hemoglobin
C is innocuous (Nagel, 2003). Only when coinherited with
sickle-cell trait to yield hemoglobin SC is the trait problematic.
Pregnancy in women with homozygous hemoglobin CC disease or C-β-thalassemia carries relatively benign associations.
Other than mild to moderate anemia, pregnancy outcomes
were not abnormal (Maberry, 1990). Supplementation with
olic acid and iron is indicated.
■ hemoglobin E
Although uncommon in the United States, hemoglobin E is
the second most requent hemoglobin variant worldwide. Te
heterozygous E trait is common in Southeast Asia. In one study,
homozygous hemoglobin E, hemoglobin E plus β-thalassemia,
or hemoglobin E trait was identied in 36 percent o Cambodians and 25 percent o Laotians (Hurst, 1983). Homozygosity or hemoglobin E is associated with little or no anemia,
hypochromia, marked microcytosis, or erythrocyte targeting.
With hemoglobin E trait, another study ound no increased
pregnancy risks other than asymptomatic bacteriuria between
1073 women and 2146 controls (Kemthong, 2016).
Conversely, doubly heterozygous E-β-thalassemia is a common cause o severe childhood anemia in Southeast Asia (aher,
2018). In a cohort study o 54 women with singleton pregnancies, a threeold greater risk o preterm birth and etal-growth
restriction was ound in aected women (Luewan, 2009). It is
unclear i hemoglobin SE disease is ominous during pregnancy.
■ hemoglobinoaty in te Newbon
Neonates with homozygous SS, SC, and CC disease can be
identied accurately at birth by cord blood electrophoresis. Te
United States Health Resources and Services Administration
(2020) recommends that all newborns be tested or sickle-cell
disease. In most states, such screening is mandated by law and
perormed routinely (Chap. 32, p. 594).
■ penatal Diagnosis
Inheritance is a concern or the etus whenever a mother and
ather carry a gene or abnormal hemoglobins that include S,Hematological Disorders 1057
ChApTEr 59
same chromosome (––/αα), whereas blacks usually have
α+-thalassemia minor in which one gene is deleted rom each
chromosome (–α/–α).
Pregnancy
Important obstetrical aspects o some α-thalassemia syndromes
depend on the number o gene deletions in a given woman.
Clinical severity closely correlates with the degree o impaired
α-globin synthesis. Te silent carrier state with one gene deletion may be associated with mild microcytic anemia (Andolina, 2020). Deletion o two genes resulting in α-thalassemia
minor is characterized by minimal to moderate hypochromic
microcytic anemia. Tis is due to either α0- or α+-thalassemia
trait, and thus genotypes may be ––/αα or –α/–α, respectively.
Dierentiation is possible only by DNA analysis (Piel, 2014).
Because no other clinical abnormalities accompany either orm
o α-thalassemia minor, it oten goes unrecognized and is usually o no maternal consequence (Hanprasertpong, 2013). Te
etus with these orms o thalassemia minor will have hemoglobin Bart (γ4) at birth, but as its levels drop, it is not replaced
by hemoglobin H (β4). Red cells are hypochromic and microcytic, and the hemoglobin concentration is normal to slightly
depressed.
Hemoglobin H disease (β4) results rom the compound heterozygous state or α0- plus α+-thalassemia with deletion o
three o our alpha genes (––/–α). With only one unctional
α-globin gene per diploid genome, the newborn will have
abnormal red cells containing a mixture o hemoglobin Bart
(γ4), hemoglobin H (β4), and hemoglobin A. O these three,
etal hemoglobin Bart (γ4) and hemoglobin H (β4) transport
oxygen poorly. Te neonate appears normal but soon develops hemolytic anemia as most o the hemoglobin Bart (γ4) is
replaced by hemoglobin H (β4). In adults, their low hemoglobin A production leads to anemia that is moderate to severe and
usually worsens during pregnancy.
Inheritance o all our abnormal α-globin genes causes
homozygous α-thalassemia, which is also called Hb Bart disease and alpha thalassemia major. Hemoglobin Bart (γ4) is
predominantly produced. Tis hemoglobin Bart has an appreciably increased anity or oxygen, transers oxygen to end
organs poorly, and is incompatible with extended survival.
Tese etuses are stillborn or are hydropic and usually die soon
ater birth.
Sonographic measurement o the etal cardiothoracic ratio
at 12 to 13 weeks’ gestation can be used to identiy aected
etuses (Lam, 1999; Zhen, 2015). Sonographic assessment o
myocardial perormance—the Tei index—in the rst hal o
pregnancy has been evaluated. Changes predate hydrops in
aected etuses (Luewan, 2013). Tese noninvasive tests may
aid pregnancy counseling.
■ Beta Talassemias
Te β-thalassemias stem rom impaired β-globin production
or α-globin instability. Genes that encode control o β-globin
synthesis are in the δγβ-gene cluster on chromosome 11 (Chap.
7, p. 129). More than 150 point mutations in the β-globin
gene have been described (Weatherall, 2010). In β-thalassemia,
β-globin production is decreased, and excess α-globin precipitate to damage cell membranes. Other orms o β-thalassemias
derive rom α-globin instability (Kihm, 2002).
Te heterozygous trait is β-thalassemia minor, and those
most commonly encountered have elevated hemoglobin A2 levels. Tis hemoglobin is composed o two α- and two δ-globins,
and concentrations are usually more than 3.5 percent. Hemoglobin F—composed o two α- and two γ-globins—also usually has increased concentrations that exceed 2 percent. Some
patients with heterozygous β-thalassemia minor do not have
anemia, and others have mild to moderate anemia characterized
by hypochromia and microcytosis.
Homozygous β-thalassemia—also called β-thalassemia
major or Cooley anemia—is a serious and requently atal disorder. Hemolysis is intense and leads to severe anemia. Many
patients become transusion dependent, and the subsequent
iron load, along with abnormally greater gastrointestinal iron
absorption, leads to hemochromatosis, which is atal in many
cases. A heterozygous orm o β-thalassemia that clinically
maniests as thalassemia intermedia produces moderate anemia.
Several treatment schemes treat β-thalassemia. Stem cell
transplantation has been used to treat β-thalassemia major
(Jagannath, 2014). Preliminary observations indicate that a
combination o thalidomide and hydroxyurea—both contraindicated in pregnancy—may be benecial to boost hemoglobin
TABLE 59-4. Genotypes and Phenotypes of α-Thalassemia Syndromes
Genotype Genotype Phenotype
Normal αα/αα Normal
α+-Thalassemia heterozygote -α/αα
αα/–α Normal; silent carrier
α+-Thalassemia homozygotea
α0-Thalassemia heterozygoteb
-α/–α
––/αα
α-Thalassemia minor—mild
hypochromic, microcytic anemia
Compound heterozygous α0/α+ ––/–α Hb H (β4) disease with moderate to
severe hemolytic anemia
Homozygous α-thalassemia ––/–– Hb Bart (γ4) disease, hydrops fetalis
aMore common in African Americans.
bMore common in Asian Americans.
} }1058
Section 12
Medical and Surgical Complications
production (Shah, 2020). Inserting a gene with a lentiviral vector into β-globin has been used to transect harvested bone
marrow stem cells (Harrison, 2019). Last, luspatercept—a
recombinant usion protein—may enhance erythroid maturation to reduce transusion requirements (Cappellini, 2020).
Pregnancy
Iron and olate supplements are given to all aected women. Tose
with β-thalassemia minor may have mild anemia during pregnancy
(Charoenboon, 2016). Tis is caused by ineective erythropoiesis
and not hemolysis. Shown in Figure 59-3 are comparable red cell
survival times in women with β-thalassemia minor compared with
those rom normally pregnant women. In some women, anemia
will worsen because slightly subnormal erythropoiesis accompanies
normal plasma volume expansion. Fetal-growth restriction has
been associated with thalassemia minor (Vaaei, 2020).
Talassemia major and some o the other severe orms were
uncommonly encountered during pregnancy beore the advent
o transusion and iron-chelation therapy. In reviews, 63 pregnancies with such management were reported and suered
no serious complications (Aessopos, 1999; Daskalakis, 1998).
Pregnancy is considered reasonably sae i maternal cardiac
unction is normal. ransusions are provided throughout pregnancy to maintain the hemoglobin concentration at 10 g/dL.
Tis is coupled with surveillance o etal growth (American
College o Obstetricians and Gynecologists, 2019b).
■ penatal Diagnosis
Diagnosis o α-thalassemia major in the etus can be accomplished by DNA analysis using molecular techniques (Piel,
2014). Fetal diagnosis o hemoglobin Bart (γ4) has been
described using capillary electrophoresis or high-perormance
liquid chromatography techniques (Sirichotiyakul, 2009).
Molecular genetic testing or HBA1 and HBA2 identies 90
percent o deletions and 10 percent o point mutations in
aected individuals (Galanello, 2011b).
Because β-thalassemia major is caused by numerous mutations, prenatal diagnosis is dicult. For a given individual,
targeted mutation analysis requires prior identication o the
amilial mutation. Te analysis is done using chorionic villus sampling and other techniques discussed in Chapter 17
(p. 344). Noninvasive testing using cell-ree etal DNA or
β-thalassemia diagnosis has been described (Xiong, 2015;
Zhang, 2019). Preimplantation genetic testing allows or identication o aected ospring prior to blastocyst transer.
pLATELET DISOrDErS
■ Tombocytoenia
Platelet abnormalities are common and may precede pregnancy, develop coincidentally during pregnancy, or be induced
by pregnancy. Trombocytopenia—dened by a platelet count
<150,000/μL—is identied in nearly 10 percent o gravidas
(American College o Obstetricians and Gynecologists, 2019c).
O these cases, 75 percent are gestational thrombocytopenia. Te
remainder is due to other causes, and HELLP syndrome is a
common one (Eslick, 2020). Trombocytopenia may be inherited or idiopathic, acute or chronic, and primary or associated
with other disorders (Table 59-5). O recent importance is
thrombocytopenia in pregnancy complicated by COVID-19
inection (ang, 2020; Zitiello, 2020).
■ Gestational Tombocytoenia
In two studies o pregnant women, platelet counts alling below
the 2.5th percentile were 116,000 and 123,000/µL (American
10
9 8 7 6 5 4 3
10 20 30 40 50 60
Days
Percent 51chromium remaining
FIGUrE 59-3 Erythrocyte-survival times with β-thalassemia
minor (black solid line) are comparable to those of normal red cells
(shaded area).
TABLE 59-5. Some Causes of Thrombocytopenia in
Pregnancy
Gestational thrombocytopenia: 75 percent
Preeclampsia and HELLP syndromes: 20 percent
Obstetrical coagulopathies: DIC, MTP
Immune thrombocytopenic purpura
Systemic lupus erythematosus and APS
Infections: viral and bacterial
Drugs
Hemolytic anemias
Thrombotic microangiopathies
Malignancies
Pseudothrombocytopenia
Renal or liver diseases
Aplastic anemia
Genetic causes
COVID-19
APS = antiphospholipid syndrome; DIC = disseminated
intravascular coagulopathy; HELLP = hemolysis, elevated
liver enzyme levels, low platelet count; MTP = massive
transfusion protocol.
From American College of Obstetricians and
Gynecologists, 2019c; Cooper, 2019; Tang, 2020.Hematological Disorders 1059
ChApTEr 59
College o Obstetricians and Gynecologists, 2019c). Approximately 1 percent have values <100,000/μL. Bleeding is only
encountered with drastically lower values. It seems reasonable
that a platelet count o <80,000/μL should trigger an evaluation
or etiologies other than incidental or gestational thrombocytopenia, which is unlikely to have a platelet count <50,000/μL.
Platelet counts decline normally across pregnancy (Fig. 4-7,
p. 62). With gestational thrombocytopenia, the platelet concentration nadir is usually evident in the third trimester and
is thought to stem rom hemodilution. Te normal increased
splenic mass o pregnancy also may contribute (Maymon,
2006; Reese, 2018).
■ Ineited Tombocytoenias
Bernard-Soulier syndrome and Glanzmann thrombasthenia lack a
platelet membrane glycoprotein, which leads to severe dysunction (Grainger, 2018). Moreover, women exposed to etal platelets
carrying this glycoprotein can develop antibodies against this etal
GPIb/IX antigen to cause alloimmune etal thrombocytopenia
(Poon, 2018). In 30 pregnancies in 18 women rom one review,
the primary postpartum hemorrhage rate was 33 percent, and hal
o women with bleeding required blood transusion (Peitsidis,
2010). Te reviewers also described six cases o neonatal alloimmune thrombocytopenia and two perinatal deaths. Close monitoring throughout pregnancy and 6 weeks postpartum is critical to
avoid potential lie-threatening hemorrhage (Prabu, 2006).
May-Hegglin anomaly is an autosomal dominant disorder
characterized by thrombocytopenia, giant platelets, and leukocyte inclusions. In one review o 26 studies containing 75
pregnancies, there were our cases o postpartum hemorrhage,
34 cases o neonatal thrombocytopenia, and two etal deaths
(Hussein, 2013).
■ Immune Tombocytoenic puua
Te primary orm—also termed idiopathic thrombocytopenic
purpura (ITP)—is usually caused by a cluster o IgG antibodies directed against one or more platelet glycoproteins.
Antibody-coated platelets are destroyed prematurely in the
reticuloendothelial system, especially the spleen (Baucom,
2019; Cooper, 2019). With IP, platelet counts range rom
10,000 to 100,000/μL (George, 2014). Although not proven,
IP is probably mediated by autoantibodies directed at plateletassociated immunoglobulins—PAIgG, PAIgM, and PAIgA.
IP classication is shown in Table 59-6 (Rodeghiero,
2009). In adults, it usually is a chronic disease that rarely
resolves spontaneously. Secondary orms o immune-mediated
chronic thrombocytopenia appear in association with systemic
lupus erythematosus, lymphomas, leukemias, and several systemic diseases. Approximately 2 percent o thrombocytopenic
patients have positive serological tests or lupus, and in some
cases, levels o anticardiolipin antibodies are high. Last, approximately 10 percent o patients with human immunodeciency
virus (HIV) have associated thrombocytopenia.
Pregnancy
Pregnancy does not raise the risk o relapse or worsen active disease. Te estimated incidence o IP complicating pregnancy
approximates 1 case in 10,000 births (Care, 2018). However,
it is not unusual or women who have been in clinical remission or several years to have recurrent thrombocytopenia during pregnancy. Although this may be rom closer surveillance,
hyperestrogenemia is also implicated.
Terapy is considered i the woman has symptomatic bleeding and the platelet count is below 30,000/μL. Te corrected
target level is 50,000/μL (American College o Obstetricians
and Gynecologists, 2019c). Primary treatment is corticosteroids,
intravenous immune globulin (IVIG), or both (Cooper, 2019).
Initially, prednisone, 1 mg/kg daily, helps suppress the phagocytic activity o the splenic monocyte–macrophage system. IVIG
given in a total dose o 2 g/kg over 2 to 5 days also is eective.
Some immunomodulating agents are avoided in pregnancy
due to teratogenicity risks. Azathioprine (Imuran) and rituximab (ruxima), however, which are used in nonpregnant
persons with IP, have been used or other conditions in
pregnancy. Last, the thrombopoietin-receptor agonists romiplostim (Nplate) and eltrombopag (Promacta) have stimulated
responses in some patients (Patras, 2020; Rosa María, 2020).
Prospective observations rom the UK Obstetric Surveillance System (UKOSS) o 107 pregnancies were described by
Care and associates (2018). Postpartum hemorrhage occurred
in hal, and in 20 percent it was severe. No neonate needed
therapy or thrombocytopenia, and no cases o intracranial hemorrhage were noted. Comont and coworkers (2018)
reported on 50 pregnancies in 39 women with IP. Hal had a
platelet count <50,000/μL, but 84 percent were treated. Tey
concluded that a third o these women were overtreated.
In pregnant women with no response to corticosteroid or
IVIG therapy, open or laparoscopic splenectomy may be eective. In late pregnancy, cesarean delivery may be necessary or
surgical exposure. Improvement usually ollows splenectomy in
1 to 3 days and peaks at approximately 8 days.
Fetal and Neonatal Effects
Pregnancy complications that are increased with IP include
stillbirth, etal loss, and preterm birth (Wyszynski, 2016).
Platelet-associated IgG antibodies cross the placenta, and
etal death rom hemorrhage occurs occasionally. Studies that
included more than 800 neonates born to women with IP cite
an intracranial hemorrhage rate <1 percent (American College
o Obstetricians and Gynecologists, 2019c). Hemorrhage was
not associated with route o delivery.
TABLE 59-6. Classification of Immune
Thrombocytopenia (ITP)
Etiology
Primary ITP: acquired immune-mediated disorder
characterized by isolated thrombocytopenia in the
absence of obvious initiating or underlying cause
Secondary ITP: thrombocytopenia due to underlying
cause/drug exposure
Duration
Newly diagnosed: persistent 3–12 months
Chronic: 12 months or more1060
Section 12
Medical and Surgical Complications
Investigators concur that etal and maternal platelet counts
lack strong correlation (George, 2009; Hachisuga, 2014).
Because o this, maternal IgG ree platelet antibody levels and
platelet-associated antibody levels have been evaluated to predict etal platelet counts. Again, however, little concurrence
with these was ound. Measuring etal platelet counts by direct
sampling is not recommended (American College Obstetricians
and Gynecologists, 2019c).
Alloimmune Thrombocytopenia
Disparity between maternal and etal platelet antigens can
stimulate maternal production o antiplatelet antibodies. Such
platelet alloimmunization can be severe, and its pathophysiology mirrors that caused by red cell antigens. Tis is discussed
in Chapter 18 (p. 352).
■ Tombocytosis
Also called thrombocythemia, thrombocytosis generally is dened
as persistent platelet counts >450,000/μL. Common causes o
secondary or reactive thrombocytosis are inection, iron deciency,
trauma, infammatory diseases, and malignant tumors (eeri,
2019). Platelet counts seldom exceed 1 million/μL in these
secondary disorders, and prognosis depends on the underlying
disease. Instead, primary or essential thrombocytosis accounts or
most cases in which platelet counts exceed 1 million/μL. It is a
clonal disorder oten due to an acquired mutation in the JAK2
gene (Spivak, 2018). Trombocytosis usually is asymptomatic,
but arterial and venous thromboses may develop, and thrombosis is associated with pregnancy complications (Rabinerson,
2007; Randi, 2014). First-line treatment is aspirin and possibly
hydroxyurea.
Normal pregnancies have been described in women whose
mean platelet counts were >1.25 million/μL. However, in a
report o 40 pregnancies in 16 women with essential thrombocythemia, almost hal had a spontaneous abortion, etal demise,
or preeclampsia (Niittyvuopio, 2004). In 63 pregnancies in 36
women cared or at the Mayo Clinic, a third had a miscarriage,
but other pregnancy complications were uncommon (Gangat,
2009). In this observational study, aspirin therapy was associated with a signicantly lower abortion rate than that in
untreated women—1 versus 75 percent, respectively. Suggested
treatments during pregnancy include aspirin, low-molecularweight heparin, and intereron α (Finazzi, 2012; Vantroyen,
2002). Intereron α therapy during pregnancy was successul
in a review o 11 women. One women had transient blindness
at midpregnancy when her platelet count was 2.3 million/μL
(Delage, 1996).
ThrOMBOTIC MICrOANGIOpAThIES
Although not a primary platelet disorder, some degree o
thrombocytopenia accompanies the thrombotic microangiopathies, which include thrombotic thrombocytopenic purpura
(TTP) and hemolytic uremic syndrome (HUS). Tese are characterized by thrombocytopenia, microangiopathic hemolysis, and
microvascular thrombosis (Konkle, 2018). Teir similarities to
HELLP syndrome allude to their obstetrical ramications.
■ Etioatogenesis
Although dierent causes account or the variable ndings
within these syndromes, clinically, they requently are indistinguishable. Inherited or idiopathic P is thought to be
caused by antibodies to or a plasma deciency o ADAMS13
(Konkle, 2018). Tis endothelium-derived metalloprotease
cleaves von Willebrand actor (vWF) to decrease its activity.
Conversely, HUS is usually rom endothelial damage incited
by viral or bacterial inections and is seen primarily in children
(George, 2014). Secondary thrombotic microangiopathies are
the most common—94 percent (Bayer, 2019). A substantial
number o all cases are pregnancy related. Other common
causes are malignancies, drugs, transplantations, and autoimmune diseases. COVID-19 inection has been reported to precipitate P (Futterman, 2020; Makatsariya, 2020).
With P, intravascular platelet aggregation stimulates a
cascade that leads to end-organ ailure. Tere is endothelial
activation and damage, but it is unclear whether this is a consequence or a cause. Elevated levels o unusually large multimers o vWF are identied with active P. Various deects
in the ADAMTS13 gene create diering clinical presentations.
In another mechanism, antibodies raised against ADAMS13
neutralize its action to cleave vWF multimers during an acute
episode. Te result is microthrombi o hyaline material containing platelets and brin within arterioles and capillaries.
When sucient in number or size, these aggregates produce
ischemia or inarction.
■ Manifestations
Trombotic microangiopathies are characterized by thrombocytopenia, ragmentation hemolysis, and organ dysunction.
P has the pentad o thrombocytopenia, hemolytic anemia,
ever, renal impairment, and neurological abnormalities. HUS
typically has more proound renal involvement and ewer neurological aberrations (Gaggl, 2018).
Trombocytopenia is usually severe, but ortunately, even
with very low platelet counts, spontaneous severe hemorrhage
is uncommon. Microangiopathic hemolysis is associated with
moderate to marked anemia, and erythrocyte transusions are
requently necessary. Te blood smear shows erythrocyte ragmentation and schizocytosis. Reticulocytes and nucleated red
blood cells counts are increased, lactate dehydrogenase (LDH)
levels are high, and haptoglobin concentrations are decreased
(Konkle, 2018). Consumptive coagulopathy, although common, is usually subtle and clinically insignicant.
■ Teatment
Te cornerstone o treatment or P is plasmapheresis with
resh-rozen plasma replacement along with glucocorticoids.
Plasma exchange removes inhibitors and replaces the ADAMS13
enzyme (George, 2014; Scully, 2019). reatment with caplacizumab (Cablivi), the anti-vWF immunoglobulin, inhibits the
interaction between ultra-large vWF multimers and platelets
(Peyandi, 2016). Tese treatments have remarkably improved
outcomes in patients with these ormerly atal syndromes. Red
cell transusions are imperative or lie-threatening anemia.Hematological Disorders 1061
ChApTEr 59
reatment is usually continued until the platelet count is normal
or 2 days. Unortunately, relapses are common. Additionally,
long-term sequelae such as renal impairment can develop (Dashe,
1998; Vesely, 2015). reatment or pregnancy-associated HUS,
which is complement mediated, is eculizumab (Soliris), the
anti-C5 humanized monoclonal antibody (Fakhouri, 2016;
Gupta, 2020).
■ pegnancy
As shown in the Appendix (p. 1228), ADAMS13 enzyme
activity declines across pregnancy by up to 50 percent (Sánchez-Luceros, 2004). Levels drop even urther with preeclampsia, and especially HELLP syndrome. Tis is consonant with
prevailing opinions that P is more commonly seen during
pregnancy. In the Parkland Hospital experience, 11 pregnancies
were complicated by these syndromes among nearly 275,000
gravidas—a requency o 1 in 25,000 (Dashe, 1998).
Some o the disparately higher incidence in pregnancy
reported by others may be rom the inclusion o women with
severe preeclampsia and eclampsia (Hsu, 1995; Magann, 1994).
Dierences that usually allow appropriate diagnosis are listed
in Table 59-7. For example, moderate to severe hemolysis is a
rather constant eature o thrombotic microangiopathies. Tis
is seldom severe with preeclampsia, even when complicated by
HELLP syndrome (Chap. 40, p. 699). Moreover, although hyaline microthrombi are seen in the liver with thrombotic microangiopathy, hepatocellular necrosis and elevated serum hepatic
transaminase levels, which are characteristic o preeclampsia, are
not a common eature (Ganesan, 2011; Sadler, 2010).
Te diagnosis o thrombotic microangiopathies, rather than
severe preeclampsia, should be clear beore initiating therapy.
Unortunately, recall that determination o ADAMS13
enzyme activity may be dicult to interpret with HELLP syndrome (Franchini, 2007). Plasmapheresis is not indicated or
preeclampsia-eclampsia complicated by hemolysis and thrombocytopenia. Importantly, delivery is imperative to reverse the preeclampsia syndrome, but thrombotic microangiopathy is not
improved by delivery (Dashe, 1998; Letsky, 2000).
Trombotic microangiopathy was previously atal in up
to hal o mothers. However, during the past two decades,
and coincidental with plasmapheresis and plasma exchange,
maternal survival rates have improved dramatically (Go,
2018; Gupta, 2020). Hunt and associates (2013) reported
that P accounted or 1 percent o maternal deaths in the
United Kingdom rom 2003 to 2008. In a systematic review
o 60 cases o pregnancy-associated HUS, two mothers died
(Gupta, 2020).
Microangiopathic syndromes are usually recurrent and requently unassociated with pregnancy. For example, seven o the
11 women described earlier at Parkland Hospital had recurrent
disease either when not pregnant or within the rst trimester
o a subsequent pregnancy. George (2009) reported recurrent
P in only ve o 36 subsequent pregnancies. In 17 women
with nonpregnant atypical HUS, recurrence developed in ve
o 32 pregnancies.
■ Longtem pognosis
Women who are diagnosed with thrombotic microangiopathy
during pregnancy are at risk or serious long-term complications (Gaggl, 2018; George, 2018). Te relapse rate is as high
as 40 percent in nonpregnant patients (Konkle, 2018). Te
described Parkland experience included a mean 9-year surveillance period (Dashe, 1998). Tese women had multiple recurrences; renal disease requiring dialysis, transplantation, or both;
severe chronic hypertension; and transusion-acquired inection. wo women died remote rom pregnancy—one rom
dialysis complications and one rom transusion-acquired HIV
inection. In the review by Gupta (2020) cited earlier, 15 percent o mothers with atypical HUS had long-term renal ailure.
In 19 women with primary atypical HUS, eight progressed to
end-stage renal disease (immermans, 2020).
INhErITED COAGULATION DEFECTS
■ hemoilias A and B
Obstetrical hemorrhage may inrequently be the consequence
o an inherited deect in a protein that controls coagulation
(Majlu-Cruz, 2020). Hemophilia and von Willebrand disease
are examples.
Hemophilia A is an X-linked recessively transmitted disorder
characterized by a marked deciency o actor VIII. Severity
refects plasma actor levels and is categorized as mild—levels
o 6 to 30 percent; moderate—2 to 5 percent; or severe—less
than 1 percent (Arruda, 2015). It is rare among women compared with men, in whom the heterozygous state is responsible or the disease. Heterozygous women have diminished
actor VIII levels, but almost invariably, the homozygous state
is requisite or hemophilia A. In a ew instances, it appears in
TABLE 59-7. Some Differential Factors between
HELLP Syndrome and Thrombotic
Microangiopathiesa
HELLP
Syndrome
Thrombotic
Microangiopathies
Thrombocytopenia Mild/mod. Mod./severe
Microangiopathic
hemolysis
(schizocytosis)
Mild Severe
ADAMTS13 deficiency Mild/mod. Severe
DIC Mild Mild
Transaminitis
(AST, ALT)
Mod./severe None/mild
Treatment Delivery Plasmapheresis
aIncludes thrombotic thrombocytopenia purpura (TTP) and
hemolytic uremic syndrome (HUS).
ADAMTS13 = ADAM metallopeptidase with thrombospondin type 1 motif, 13; AST = aspartate transaminase; ALT =
alanine transaminase; DIC = disseminated intravascular
coagulopathy; HELLP = hemolysis, elevated liver enzyme
levels, low platelet count; Mod. = moderate.1062
Section 12
Medical and Surgical Complications
women spontaneously rom a newly mutated gene. Pregnancyassociated acquired hemophilia A rom antibodies may result in
severe bleeding-related morbidity (engborn, 2012). Christmas
disease or hemophilia B is caused by severe deciency o actor
IX and has similar genetic and clinical eatures.
Pregnancy
Te risk o obstetrical bleeding with hemophilia is directly
related to actor VIII or IX levels. Aected women have a range
o activity that is determined by random X-chromosome inactivation—lyonization—although activity is expected to average
50 percent (Letsky, 2000). Levels below 10 to 20 percent pose
hemorrhage risks. I levels all to near zero, this risk is substantial. Pregnancy does aord some protection, however, because
concentrations o both these clotting actors rise appreciably
during normal pregnancy (Appendix, p. 1228). reatment with
desmopressin can stimulate actor VIII release. Risks are urther
reduced by avoiding lacerations, minimizing episiotomy use,
and maximizing postpartum uterine contractions. Operative
vaginal delivery and cesarean delivery pose bleeding risks.
A ew articles describe pregnancy courses. Kadir and colleagues (1997) reported that 20 percent o carriers had postpartum hemorrhage. Guy and associates (1992) reviewed ve
pregnancies in women with hemophilia B, and in all, outcomes
were avorable. Tey recommended actor IX administration
i levels are below 10 percent. Desmopressin in selected cases
has reduced obstetrical bleeding complications (rigg, 2012).
I a male etus has hemophilia, the risk o hemorrhage increases
ater delivery in the neonate. Tis is especially true i circumcision is attempted.
Related to preconceptional counseling, most women with
hemophilia A or B carry one aected allele and the other X
chromosome is normal. Tese individuals will have all sons
aected by the disease, and hal o her daughters will be carriers. Rarely, a woman may carry two abnormal alleles, in which
case all daughters will be carriers and all o her sons will inherit
the disease. Prenatal diagnosis o hemophilia is possible in some
amilies using chorionic villus biopsy (Chap. 17, p. 346). Preimplantation genetic testing or hemophilia was reviewed by
Lavery (2009).
■ Facto VIII o IX Inibitos
Rarely, antibodies directed against actor VIII or IX are
acquired and may lead to lie-threatening hemorrhage. Patients
with hemophilia more commonly develop antibodies, and their
acquisition in patients without hemophilia is extraordinary. It
has been identied rarely in women during the puerperium
(Santoro, 2009). Te prominent clinical eature is severe,
protracted, repetitive hemorrhage rom the reproductive tract
starting a week or so ater an apparently uncomplicated delivery
(Gibson, 2016). Te activated partial thromboplastin time is
markedly prolonged. reatment has included multiple bloodcomponent transusions, immunosuppressive therapy, and
attempts at various surgical procedures, especially curettage and
hysterectomy. A recombinant activated actor VII (NovoSeven)
stops bleeding in up to 75 percent o patients with these inhibitors (Arruda, 2015; Gibson, 2016).
■ Von Willeband Disease
At least 20 heterogeneous clinical disorders involve aberrations
o actor VIII complex and platelet dysunction and collectively
are termed von Willebrand disease (vWD). Tese abnormalities
are the most requently inherited bleeding disorders, and their
prevalence is as high as 1 to 2 percent (Arruda, 2015; Punt,
2020). Most von Willebrand disease variants are inherited as
autosomal dominant traits. ypes I and II are the most common, and type I accounts or 75 percent. ype III, which is the
most severe, is a recessive trait. Although most cases o acquired
vWD develop ater age 50 years, some have been reported in
pregnant women (Lipkind, 2005).
Pathogenesis
Te von Willebrand actor (vWF) is a series o large, plasma
multimeric glycoproteins that orm part o the actor VIII complex. It is essential or normal platelet adhesion to subendothelial collagen and ormation o a primary hemostatic plug. It
also plays a major role in stabilizing the coagulant properties
o actor VIII. Factor VIII, a glycoprotein, is synthesized by
the liver. Te von Willebrand precursor, which is present in
platelets and plasma, is instead synthesized by endothelium and
megakaryocytes. Te von Willebrand actor antigen (vWF:Ag)
is the antigenic determinant measured by immunoassays.
Symptomatic women typically present with easy bruising,
epistaxis, mucosal hemorrhage, heavy menses, and excessive
bleeding with trauma or surgery. Te classic autosomal dominant orms usually cause symptoms in the heterozygous state.
With vWD, laboratory eatures oten include a prolonged bleeding time, prolonged partial thromboplastin time, decreased
vWF antigen levels, decreased actor VIII immunological and
coagulation-promoting activity, and inability o platelets rom
an aected person to react to various stimuli.
Although most patients with vWD have heterozygous variants and associated minor bleeding complications, the disease
can be severe. Moreover, homozygous ospring develop serious clotting dysunction. Chorionic villus sampling with DNA
analysis to detect the missing genes has been described, but
the specic genetic mutation must be known. Some authorities recommend cesarean delivery to avoid trauma to a possibly
aected etus i the mother has severe disease.
Pregnancy
During normal pregnancy, maternal levels o both actor VIII
and vWF antigen increase substantively (Appendix, p. 1228).
Because o this, pregnant women with vWD oten develop normal levels o actor VIII coagulant activity and vWF antigen,
although their measured bleeding time still may be prolonged
(Delbrück, 2019). I actor VIII activity is very low or i there
is bleeding, treatment is recommended. Desmopressin by inusion transiently increases actor VIII and vWF levels (Arruda,
2015). With signicant bleeding, 15 or 20 units o cryoprecipitate are transused every 12 hours. Alternatively, actor VIII
concentrates (Alphanate, Humate-P) that contain high-molecular-weight vWF multimers may be given. Lubetsky and colleagues (1999) described continuous inusion with Humate-P
in a woman during a vaginal delivery. According to Chi andHematological Disorders 1063
ChApTEr 59
coworkers (2009), conduction analgesia can be provided saely
i coagulation deects have corrected or i hemostatic agents are
administered prophylactically.
Pregnancy outcomes in women with vWD are generally
good, but postpartum hemorrhage is common. In one systematic review, with more than 800 deliveries, the postpartum
hemorrhage incidence was 33 percent (Punt, 2020). In a database review o more than 2200 deliveries complicated by vWD,
this incidence was only about 5 percent (O’Brien, 2020). From
two reviews, postpartum hemorrhage may be primary and at
the time o delivery, or it may have a delayed onset (Makhamreh, 2021a,b).
■ Ote Facto Deficiencies
In general, the activity o most procoagulant actors rises across
pregnancy (Appendix, p. 1228). Factor VII deciency is a rare
autosomal recessive disorder. Levels o this actor increase
during normal pregnancy, but these may rise only mildly in
women with actor VII deciency (Fadel, 1989). A systematic
review o 94 births ound no dierence in postpartum hemorrhage rates with or without prophylaxis with recombinant actor VIIa (Baumann Kreuziger, 2013).
Factor X or Stuart-Prower actor deciency is rare and inherited as an autosomal recessive trait. Factor X levels typically rise
by 50 percent during normal pregnancy. Despite this, adverse
pregnancy outcome are common. Spiliopoulos and coworkers
(2019) reported 31 pregnancies in 19 women. Tey described
a high rate o preterm birth, perinatal mortality, and postpartum hemorrhage. Conversely, Nance and colleagues (2012)
described 24 pregnancies, o which 18 resulted in a healthy
baby. reatment is with plasma-derived actor X, resh-rozen
plasma, or prothrombin complex concentrates.
Factor XI deciency is inherited as an autosomal recessive
trait in most amilies. It maniests as severe disease in homozygotes but only as a minor deect in heterozygotes. It is most
prevalent in Ashkenazi Jews and is rarely seen in pregnancy. In
one review o 105 pregnancies rom 33 aected women, 70 percent had an uneventul pregnancy and delivery (Myers, 2007).
Authors recommended peripartum treatment with actor XI
concentrate or cesarean delivery and advised against epidural
analgesia unless actor XI is given. From another review, actor
XI levels and bleeding severity correlated poorly in women with
severe deciency (Martin-Salces, 2010). Wiewel-Verschueren
and associates (2016) perormed a systematic review o 27 studies with 372 women and reported that 18 percent had postpartum hemorrhage.
Factor XII deciency is another autosomal recessive disorder that rarely complicates pregnancy. A greater incidence o
thromboembolism is encountered in nonpregnant patients
with this deciency.
Factor XIII deciency is an autosomal recessive trait and
may be associated with maternal intracranial hemorrhage
(Boutteroy, 2020). In their review, Kadir and associates
(2009) cited an increased risk o recurrent miscarriage and
placental abruption. It has also been reported to cause umbilical cord bleeding (Odame, 2014). reatment is resh rozen
plasma. Naderi and colleagues (2012) described 17 successul
pregnancies in women receiving weekly prophylaxis with actor XIII concentrate.
Fibrinogen abnormalities—either qualitative or quantitative—also may cause coagulation abnormalities. Autosomally
inherited abnormalities usually involve the ormation o a
unctionally deective brinogen—commonly reerred to as
dysbrinogenemia. Familial hypobrinogenemia and sometimes
abrinogenemia are inrequent recessive disorders. Our experience suggests that hypobrinogenemia represents a heterozygous autosomal dominant state. Te thrombin-clottable protein
level in these patients typically ranges rom 80 to 110 mg/dL
when nonpregnant. Cai and coworkers (2018) described successul outcomes in aected women in whom brinogen or
plasma inusions were given throughout pregnancy.
ThrOMBOphILIAS
Several important regulatory proteins act as inhibitors at strategic sites in the coagulation cascade to maintain blood fuidity.
Inherited deciencies o these inhibitory proteins are caused
by gene mutations. Because they may be associated with recurrent thromboembolism, they are collectively reerred to as
thrombophilias. Tese are discussed in Chapter 55 (p. 976) and
reviewed by the American College o Obstetricians and Gynecologists (2020).
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