10 1016@j Blre 2019 100638 PDF

Journal Pre-proof
Thrombocytopenia in pregnancy: Diagnosis and approach to

management
Allyson M. Pishko, Lisa D. Levine, Douglas B. Cines
PII: S0268-960X(19)30152-3
DOI: https://doi.org/10.1016/j.blre.2019.100638
Reference: YBLRE 100638
To appear in: Blood Reviews
Please cite this article as: A.M. Pishko, L.D. Levine and D.B. Cines, Thrombocytopenia in
pregnancy: Diagnosis and approach to management, Blood Reviews(2019), https://doi.org/
10.1016/j.blre.2019.100638
This is a PDF file of an article that has undergone enhancements after acceptance, such
as the addition of a cover page and metadata, and formatting for readability, but it is
not yet the definitive version of record. This version will undergo additional copyediting,
typesetting and review before it is published in its final form, but we are providing this
version to give early visibility of the article. Please note that, during the production
process, errors may be discovered which could affect the content, and all legal disclaimers
that apply to the journal pertain.
© 2019 Published by Elsevier.

Journal Pre-proof
Thrombocytopenia in Pregnancy: Diagnosis and Approach to Management

Allyson M. Pishko1,* , Lisa D. Levine2, Douglas B. Cines 1,3
1
Department of Medicine, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA, USA
2
Maternal and Child Health Research Center, Department of Obstetrics and Gynecology,
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
1,3
Departments of Pathology and Laboratory Medicine and Medicine, Perlman School of
Medicine, University of Pennsylvania, Philadelphia, PA, USA
* Correspondence:
3400 Spruce Street 3rd floor Dulles
of
Philadelphia, PA 19104, USA
Email: apishko@pennmedicine.upenn.edu
ro
-p
re
lP
na
ur
Jo
Journal Pre-proof
Abstract:
Thrombocytopenia during pregnancy presents unique challenges for the hematologist.
Obstetricians generally manage many of the pregnancy-specific etiologies, ranging from the
benign (gestational thrombocytopenia) to the life-threatening (preeclampsia; hemolysis,
elevated liver enzymes and low platelets syndrome; and acute fatty liver of pregnancy).
However, hematologists may be consulted for atypical and severe presentations and to help
manage non-pregnancy specific etiologies, including immune thrombocytopenia, thrombotic
thrombocytopenic purpura, hemolytic uremic syndrome and antiphospholipid syndrome, among
others, in which maternal and fetal risks must be considered. This review provides a general
approach to the diagnosis and management of thrombocytopenia in pregnancy for the
of
consulting hematologist.
ro
-p
Keywords: Thrombocytopenia; pregnancy; immune thrombocytopenia; gestational
thrombocytopenia; preeclampsia; thrombotic thrombocytopenic purpura; von Willebrand
re
disease; hemolytic uremic syndrome
lP
na
ur
Jo
Journal Pre-proof
1. Introduction
Thrombocytopenia, defined as a platelet count less than 150 x 109/L, develops during 5-10% of
pregnancies [1]. Thrombocytopenia in pregnancy presents three major clinical challenges,
including the need to: (1) identify when maternal thrombocytopenia is indicative of a health-
threatening disorder, (2) obtain an adequate platelet count for the hemostatic challenges of
delivery, and (3) help evaluate the risk of thrombocytopenia in the neonate. We will present our
approach to the differential diagnosis of thrombocytopenia in pregnancy. We will review the
pathogenesis, diagnosis and management of the pregnancy-specific causes of
thrombocytopenia, including gestational thrombocytopenia (GT); pre-eclampsia (PEC);
hemolysis, elevated liver enzymes and low platelets syndrome (HELLP); and acute fatty liver of
of
pregnancy (AFLP). We will consider other causes of thrombocytopenia that may present during
ro
pregnancy or as pre-existing conditions complicating pregnancy, including immune
thrombocytopenia (ITP), Evans syndrome, type 2B von Willebrand Disease (vWD), thrombotic
-p
thrombocytopenic purpura (TTP), atypical hemolytic uremic syndrome (aHUS), and
antiphospholipid antibody syndrome (APS). We will also review general recommendations for
re
management of delivery and the post-partum period.
lP
2. General Approach to Evaluation of Thrombocytopenia in Pregnancy

2.1 History and physical examination
na
The differential diagnosis of thrombocytopenia in pregnancy is impacted by the time of

onset (see section 2.2 below). Identifying the duration of preceding symptoms of bleeding or
ur
bruising may provide important insights when pre-gestation platelet counts are not available.
Exposures (medications, supplements, alcohol, recreational drugs), concomitant symptoms
Jo
suggesting infection or multi-system disease, family history suggestive of an inherited

thrombocytopenia, and personal or family history of thrombosis or multiple miscarriages should
be part of the initial assessment.
Physical findings that might impact diagnosis and management include: extent of
bleeding/bruising (concern for severe thrombocytopenia/concurrent coagulopathy), hypertension
(concern for PEC/HELLP), arthritis/serositis (concern for autoimmune disorder), fever (concern
for infection/inflammation or more rarely TTP), lymphadenopathy or hepatosplenomegaly
(concern for malignancy), or neurologic findings (concern for TTP/severe PEC).
2.2 Etiologies by Trimester

Journal Pre-proof
The trimester when thrombocytopenia develops can also provide an important clue to etiology
(figure 1). A gradual decline in platelet count occurs in many women starting in the middle of
the second trimester, i.e. gestational thrombocytopenia. A decline prior to this time suggests an
etiology other than gestational thrombocytopenia as does severe thrombocytopenia (platelets
<30-50 x 109/L) developing suddenly closer to term [1].
2.3 Laboratory Testing

Isolated thrombocytopenia should be documented based on a complete blood count and
distinguished from an artifact of counting caused by ethylenediaminetetraacetic acid (EDTA)-
induced platelet clumping through examination of the peripheral blood smear. The blood smear
of
should be evaluated carefully for abnormalities in the erythrocytes (e.g. schistocytes, tear drops)
ro
or leukocytes (hyper/hyposegmentation), or immature/dysplastic/monomorphic populations
suggesting a systemic hematologic disorder. Evaluation of platelet size may distinguish the
-p
small platelets of Wiskott-Aldrich syndrome from the giant platelets typical of some other
congenital platelet disorders. Other studies indicated by history and initial evaluation may
re
extend to: 1) markers of hemolysis, e.g. lactic acid dehydrogenase (LDH), haptoglobin, and
reticulocyte counts (TTP, HELLP); 2) a basic metabolic panel and tests of liver function (HELLP,
lP
AFLP); 3) PT/PTT and fibrinogen (disseminated intravascular coagulation DIC, associated with
HELLP or placental abruption); testing for HIV, hepatitis B, hepatitis C and thyroid function (ITP)
na
4) assessment for antiphospholipid antibodies (APS); and 5) evaluation for vWD (personal or
family history of thrombocytopenia and bleeding). The impact of laboratory studies on the
ur
diagnosis of thrombocytopenia in pregnancy is outlined in table 1.

Jo
3. Gestational Thrombocytopenia
3.1 Definition and Incidence
Gestational thrombocytopenia (GT) is the most common etiology of thrombocytopenia in
pregnancy. The diagnosis is considered when a platelet count below 150 x 109/L develops after
the second trimester of pregnancy in the absence of other hematologic or clinical abnormalities.
An alternative etiology should be sought, especially when thrombocytopenia is detected earlier
in pregnancy. When a pre-gestational platelet count is not available to establish onset, it is
helpful to consider that platelet counts in women with GT usually trend downwards gradually
until delivery but generally remain above 80 x 109/L [2]. More severe thrombocytopenia is
reported infrequently (0.1% of uncomplicated pregnancies in one large study) [2].
Thrombocytopenia developing earlier in pregnancy, platelet counts of <80 x 109/L, and
Journal Pre-proof
precipitous falls in platelet count all warrant investigation into potentially more serious alternative
diagnoses.
3.2 Pathogenesis
The pathogenesis of GT is unclear. Hemodilution caused by the increased plasma volume that
develops during pregnancy may contribute as may sequestration of platelets in the placenta [2]
and spleen [2-4], though compelling supporting evidence for either process is lacking.
3.3 Diagnosis
There is no specific laboratory test to diagnose GT. GT is therefore a diagnosis of exclusion
of
based on: 1) Absence of inter-gestational thrombocytopenia; 2) Time of onset; 3) Severity of
ro
thrombocytopenia; 4) Exclusion of other diagnoses, which may not be possible in some women
who present with ITP late in gestation. In a large retrospective study, platelet counts recovered
-p
spontaneously at a mean of 7.1 weeks following uncomplicated pregnancy [2], consistent with
prior studies [1, 5].
re
3.4 Management
lP
GT does not confer an increased risk of maternal bleeding. Nor are special precautions
required for delivery if the diagnosis is secure, as neonates are not at increased risk of being
na
born with clinically significant thrombocytopenia [6] [7]. Recurrence rates may exceed 50% [6],
but affected women are not predisposed to develop hypertension, renal insufficiency, PEC or
ur
other serious complications during subsequent pregnancies.

Jo
4. Preeclampsia
Preeclampsia (PEC) is a syndrome defined by the new onset of hypertension after 20 weeks of
gestation (systolic blood pressure ≥140 or diastolic blood pressure ≥ 90 mmHg) and proteinuria.
Severe preeclampsia is characterized by significant end organ dysfunction, including:
thrombocytopenia (platelets <10 x 109/L), impaired liver function, new onset renal insufficiency
(creatinine >1.2 mg/dL), pulmonary edema, cerebral or visual disturbances, and/or persistent
systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥110 mmHg [8]. The diagnosis
can be made even in the absence of proteinuria. PEC complicates 3.8% of pregnancies in the
United States, with severe PEC and/or eclampsia occurring in 1.4% of pregnancies. PEC may
Journal Pre-proof
occur more commonly in women with autoimmune disease such as lupus and antiphospholipid
antibody syndrome [9, 10]. Generally, the onset is in the late second or third trimester [11].
4.2 Pathogenesis
The pathogenesis of PEC is incompletely understood but might involve abnormal placental
angiogenesis and vascular function (reviewed in [11] and [12]) with narrowing of arterioles
leading to severe placental ischemia in the most severe cases [12]. Several pathologic features
of PEC occur including: (1) incomplete remodeling of maternal spiral arteries in the uterus; (2)
release of antiangiogenic factors from the ischemic placenta into the maternal circulation; (3)
vasospasm and impaired blood supply to target organs, including uterus and placenta. The
of
mechanism by which PEC leads to thrombocytopenia is also unclear. Syncytiotrophoblasts from
ro
affected placentas shed extracellular vesicles that augment platelet activation, which
presumably also accelerates their clearance [13], but undoubtedly additional mechanisms are
operative.
-p
re
4.3 Diagnosis
PEC should be considered when de novo hypertension is discovered after 20 weeks gestation.
lP
The American College of Obstetrics and Gynecology (ACOG) and National Institute for Health
and Care (NICE) guidelines provide an algorithm to evaluate hypertension in pregnancy and to
na
diagnose PEC [14-16]. Evaluation for proteinuria (with a 24-hour urine protein assessment or
spot urinary protein-creatinine ratio) is part of the diagnostic evaluation, but the proteinuria
ur
(>300 mg/day) is not required if signs of maternal organ dysfunction are present [11, 17]. While
fetal growth restriction may result from PEC, it is no longer part of the diagnostic criteria for
Jo
severe PEC [8].

While obstetricians are typically on the frontlines of management, hematologists may be
consulted when there is diagnostic uncertainly. Thrombocytopenia is a feature of PEC with
severe features, but platelet counts are typically above 100 x 1009/L and rarely below 50 x 109/L
[1]. Some schistocytes may be seen on the peripheral blood smear, but overt hemolysis should
raise the suspicion for HELLP or TTP. Elevation of creatinine can occur with severe PEC, but it
should also cause the clinician to consider alternate etiologies such as TTP/aHUS. Mild
elevation of liver function tests may be present with more severe elevations indicative of HELLP.
Biochemical findings of disseminated intravascular coagulation (DIC) may occur, but overt
bleeding or thrombosis is rare [1, 18]. Deterioration in clinical or laboratory parameters or failure
Journal Pre-proof
to improve by 48-72 hours after delivery should prompt consideration of an alternative

diagnosis, such as TTP or aHUS [1].
4.4 Management
Recommendations for management are based on the gestational age at diagnosis [8]
Definitive management involves delivery of the placenta [15]. However, in some patients who
are <34 weeks gestation, inpatient expectant management can be considered until 34 weeks.
Some contraindications to expectant management include systolic blood pressure ≥170 mmHg,
diastolic ≥110 mmHg despite antihypertensive medications, HELLP, pulmonary edema, or
persistent neurological symptoms (e.g. headache). For all women diagnosed with severe PEC
of
≥34 weeks, delivery is indicated. Aside from delivery, management of PEC includes treatment
ro
of severe hypertension with intravenous labetalol, hydralazine, or oral short acting nifedipine [8].
Bed rest is not advisable and fluids are administered cautiously [8]. In patients with eclampsia
-p
or severe preeclampsia, magnesium sulfate should be administered to prevent seizures; there is
no consensus regarding the use of magnesium sulfate for prophylaxis if severe features are not
re
present [15]. Cesarean delivery should be reserved for routine obstetrical indication or
progressively worsening disease.
lP
Many new therapies and prevention strategies for PEC are currently under investigation. For
na
example, in a murine model, the HMG-CoA reductase inhibitor, pravastatin, reduced the release
of antiangiogenic factors (soluble fms-like tyrosine kinase 1 (sFLT1) and soluble endoglin
ur
(sENG)) and increased vascular endothelial growth factor (VEGF) [19]. A pilot study of
pravastatin given to women at high risk of developing PEC demonstrated safety in pregnancy
Jo
[20]. There is now an ongoing randomized clinical trial of pravastatin as a preventative strategy
in women at high-risk for PEC (NCT01717586). Sildenafil a (phosphodiesterase 5 inhibitor) also
showed promise in murine models of PEC to enhance fetal growth, but the multicenter study in
women with severe fetal growth restriction was stopped early due to adverse events in the
intervention group [21]. New agents such as recombinant VEGF121 and recombinant P1GF
(ligand of sFLT1) decreased blood pressure and proteinuria in murine models, but have yet to
be subjected to clinical trials [22].
4.5 Counseling for future pregnancies

PEC occurring with future pregnancies is common with recurrence ranging from 20-100%.
Early gestational age at diagnosis in a prior pregnancy (e.g. preterm), presence of chronic
Journal Pre-proof
hypertension, and >1 prior pregnancy with PEC all significantly increase the risk of recurrence.
The risk is generally highest with the first pregnancy and decreases with subsequent
pregnancies [23, 24]. This led to the hypothesis that there is maternal adaptation to antigens
from a specific partner during subsequent pregnancies. However, a large epidemiologic study
questioned this paradigm, as women with partner changes also had longer intervals between
births. When this difference in birth interval is taken into account, change in paternity was no
longer associated with a clear increased risk of recurrence [23]. The American College of
Obstetricians and Gynecology (ACOG) and United States Preventative Task Force (USPTF)
recommends the use of aspirin (81 mg/day) as prophylaxis in patients at high risk of PEC (see
table 2) beginning between 12 and 28 weeks of gestation [25]. This recommendation is based
of
in part on pooled data from 15 randomized control trials that suggested a decrease in the
ro
relative risk of PEC when aspirin was given compared to standard care [0.90 (95% CI 0.84–
0.97)] [26]. A more significant benefit was found in the Combined Multimarker Screening and
-p
Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention
(ASPRE) trial of aspirin 150 mg versus placebo, with PEC occurring in 1.6% of patients in the
re
aspirin group versus 4.3% in the placebo group (adjusted odds ratio 0.38, p=0.004)[27]. Low-
molecular weight heparin has not been shown to prevent recurrence [28]. One clinical criterion
lP
for antiphospholipid antibody syndrome is the occurrence one or more premature births of a
morphologically normal neonate due to early onset eclampsia or severe PEC. Therefore,
na
screening for antiphospholipid antibodies and a lupus anticoagulant may be considered in this
setting (see section 10 below) [29]. Vitamin D supplementation may have a protective effect
ur
[30, 31]. Calcium supplementation (≥1 gram/day) may also be protective, particularly in patients
at risk for low dietary intake. Surprisingly, a recent randomized control trial did not find an effect
Jo
of early calcium supplementation (prior to 20 weeks gestation). Potential reasons for lack of an
effect include suboptimal compliance, study size, and various gestational ages at initiation and
further population studies are needed [32].
5. Hemolysis, elevated liver enzymes, low platelets syndrome

The syndrome of hemolysis, elevated liver enzymes, low platelets (HELLP) may be a severe
variant of PEC with high morbidity and mortality. HELLP occurs in approximately 0.2-0.8% of all
pregnancies, and up to 8-24% of patients with severe PEC or eclampsia will develop HELLP in
some series [33]. While 70-80% of cases of HELLP develop in the context of PEC, there are
Journal Pre-proof
reports of HELLP occurring without PEC [33, 34]. HELLP is more likely to occur during twin
gestations [35].
5.2 Pathogenesis
It is unclear why some women with PEC develop HELLP. Placental pathology is similar
(reviewed in [34]). A more intense inflammatory response (higher maternal C-reactive protein,
interleukin-6, and TNF- β) [34] and sustained activation of the alternative pathway of
complement activation due to genetic defects in complement regulatory proteins may contribute
[36, 37].
of
5.3 Diagnosis
ro
Most cases (70%) of HELLP develop between 27 and-37 weeks gestation and the onset may be
abrupt. Thirty percent of cases manifest within 48 hours after of delivery [38]. The diagnosis
-p
should be considered when progressive thrombocytopenia, overt hemolysis, and worsening
hepatic function develop in the setting of PEC [1]. Several classification schemas (e.g. the
re
Tennessee classification system and the Mississippi Triple-class HELLP system) have been
developed to help identify disease onset and severity [38]. Included in these classification
lP
schemes are thrombocytopenia, LDH elevation and liver function testing elevation (AST/ALT).
Women with HELLP are at an increased risk for subcapsular liver hematomas and therefore a
na
liver ultrasound should be considered in a patient with severe PEC or HELLP and persistent
right upper quadrant pain.
ur
5.4 Management
Jo
Urgent delivery is the cornerstone of management. Management of maternal hypertension and

magnesium to prevent seizures may be required. Intrauterine fetal demise is a risk in women
with severe PEC and HELLP. Neonatal morbidity is directly related to gestational age at
delivery. There are no established interventions that support an expectant approach. Cesarean
delivery should be reserved for routine obstetrical indication or progressively worsening disease.
In a meta-analysis, it was reported that 7.2% of women with HELLP had a recurrence during
subsequent pregnancies and 36.3% developed either another hypertensive syndrome or fetal
growth restriction [39].
6. Acute fatty liver of pregnancy

Journal Pre-proof
Acute fatty liver of pregnancy (AFLP) is characterized by the rapid onset of hepatic failure.
AFLP is far less common than PEC or HELLP, occurring in 1/7000-1/15,000 pregnancies, with
an increased incidence in multigravidas [40].
6.2 Pathogenesis
AFLP is characterized by fatty infiltration of the liver. The pathogenesis is incompletely
understood. Free fatty acids normally increase during pregnancy, presumably to support fetal
growth. Defective maternal-fetal metabolism caused by maternal, in some cases accompanied
by fetal, deficiencies in 3-hydroxyacyl-CoA dehydrogenase (LCHAD) or, less frequently, other
enzymes involved in mitochondrial metabolism of fatty acids leads to accumulation of
of
intermediates in metabolic pathway [40, 41]. If the fetus is homozygous for the deficiency,
ro
hepatotoxicity may develop in a heterozygous mother. However, as not all mutations that cause
LCHAD deficiency are associated with AFLP, there may be other factors that modulate the
phenotype [40].
-p
re
6.3 Diagnosis
AFLP typically presents in the third trimester (see Swansea criteria for diagnosis, table 3)
lP
[42]. Fatty infiltration may be evident on ultrasound [41]. Microvesicular fatty infiltration of the
hepatocytes is often seen on liver biopsy, but this is rarely required for diagnosis [40]. In severe
na
cases, impaired synthesis of fibrinogen and other coagulation proteins predisposes to bleeding,
but severe thrombocytopenia is infrequent [1]. Hypoglycemia is a key feature of severe disease
ur
that helps to distinguish AFLP from other causes of thrombocytopenia in pregnancy. Severe
coagulopathy and encephalopathy are more common and hypertension is less common in
Jo
AFLP than in HELLP [43]. Additionally, there is often a greater increase in bilirubin relative to
serum transaminase levels in AFLP than is seen in HELLP [44].
6.4 Management
Prompt delivery is needed to prevent rapid progression, regardless of gestational age. There is
no contraindication to a vaginal delivery if it can be achieved in a reasonable time period (often
within 24 hours). Supportive management with packed red blood cells and fresh frozen plasma
to raise fibrinogen levels, typically ≥200 mg/dL, is advised for all women, but especially prior to
cesarean section. Antithrombin III concentrate may be useful in severe cases [1]. Clinicians
must be vigilant for post-partum hemorrhage given the associated coagulopathy.
Journal Pre-proof
7. Immune thrombocytopenia
Immune thrombocytopenia (ITP) is a syndrome caused by autoantibodies that accelerate
platelet clearance and inhibit their production [45]. ITP accounts for approximately 3% of all
cases of thrombocytopenia in pregnancy, but is the most common cause of a platelet count less
than 50 x 109/L in the first or second trimesters [1]. Autoimmune hemolytic anemia may occur
simultaneously with ITP or before or after this diagnosis, in a condition termed Evans syndrome,
described separately (section 8) [46].
7.2 Pathogenesis
of
Thrombocytopenia in ITP is caused by macrophage-mediated clearance of antibody-coated
ro
platelets, predominantly in the spleen and liver, combined with insufficient compensatory
platelet production. Levels of plasma thrombopoietin (TPO), which binds to bone marrow
-p
megakaryocytes and is cleared along with the ITP platelets, are typically normal or marginally
elevated [47, 48]. Ten-20% of cases of ITP occur in the context of persistent
re
infection/inflammation (HIV, hepatitis C, H pylori), a systemic autoimmune disorder (systemic
lupus (SLE), common variable immune deficiency, APLS, or an immune thyroid disorder) or a B-
lP
cell neoplasm (most commonly chronic lymphocytic leukemia), but most presentations occur in
isolation and the exact etiology is unknown [45].
na
7.3 Diagnosis
ur
Diagnosis of ITP is based on the constellation of isolated thrombocytopenia, an otherwise

normal peripheral blood smear, and the absence of evidence pointing toward another
Jo
hematologic disorder such as recent infection, inherited thrombocytopenia and potential drug-
induced causes. However, microcytic anemia may be seen due to iron-deficiency, prevalent in
pregnant patients. A robust response to ITP-directed therapy is the strongest diagnostic
criterion [1]. It is difficult to distinguish ITP from GT when a woman presents with platelet counts
>100 x 109/L in the late second or in the third trimester when the pre-gestational platelet count is
unknown. A report that serum TPO levels may help in distinguishing ITP versus gestational
thrombocytopenia requires validation [49]. Unaided recovery of the platelet count within 12
weeks of delivery is supportive of the diagnosis of GT.
7.4 Maternal considerations prior to gestation

Journal Pre-proof
Pregnancy is not contraindicated unless the mother has a recent history of significant bleeding
and a platelet count below 20 x 109/L that is either unresponsive to therapy or requires
potentially teratogenic therapy. Pregnancy has no known long-term impact on the clinical
course of ITP post-delivery [50]. As platelet counts fall during normal gestation, it is not
surprising that some women with ITP develop more severe thrombocytopenia and have a
greater need for therapy during pregnancy [51]. Alternative treatments must be considered in
women whose pre-gestational disease has been managed with thrombopoietin receptor
agonists (TRAs), now used as second line therapy in many countries. This can be a challenge
as some of these patients responded poorly or were intolerant of other treatment modalities. In
one study, women who were post-splenectomy had higher platelet counts and required fewer
of
interventions than those who had been managed medically [52].
ro
7.5 Management during gestation-First line therapies
-p
Therapy is not required for a platelet count ≥30 x 109/L in the absence of bleeding or
comorbidities until a woman is nearing delivery [3]. Platelet counts should be monitored at least
re
monthly and more frequently if unstable. More frequent monitoring is also indicated starting at
34 weeks gestation, especially if the platelet count is <80 x 109/L, which is the threshold often
lP
used by anesthesiologists for neuraxial anesthesia [3], and to avoid the need for platelet
transfusions or other emergency measures at the time of delivery.
na
Potential therapies for ITP and considerations for pregnancy are summarized in table 4.
Corticosteroids or IV immunoglobulin (IV IG) are first line therapies [51, 53]. Corticosteroids are
ur
generally considered to be safe in pregnancy. However, high-dose corticosteroid therapy are

often not tolerated and are associated with an increased risk of gestational diabetes,
Jo
hypertension or emotional lability in the mother and has been associated with an increased risk
of cleft palate in the fetus when given in the first trimester [54] [55]. Therefore, repeated
infusions of IV IG may be preferable in this setting [1]. Notwithstanding the theoretical risk,
thrombosis has not been reported as a frequent complication in studies comparing IV IG to
corticosteroids in pregnancy [51].
7.6 Management during gestation-Second line therapies

The response to IV IG (38%) and corticosteroids (39%) may be lower in pregnancy than in non-
pregnant patients with ITP, perhaps because dosing is limited to lessen toxicity [51]. There is
little data on the safety and efficacy of second-line therapies for ITP during pregnancy [56].
Journal Pre-proof
Splenectomy has been performed safely in the second trimester for treatment of ITP, but is
rarely required [57].
It is recommended that pregnancy be avoided for 6-12 months after rituximab because
of transplacental transport [58] (FDA label). However, rituximab has been given during
pregnancy to women with hematologic malignancies without compelling evidence of
teratogenicity to date. Data from a global rituximab drug safety database revealed that 12.2%
(11/91) neonates with rituximab exposure were born with hematologic abnormalities (most
commonly B-cell depletion and/or lymphocytopenia [58]), none of whom experienced infectious
complications [58]. Azathioprine and cyclophosphamide and cyclosporine have been used to
manage transplantation or to treat rheumatologic conditions during pregnancy [59] [60], with an
of
acceptable safety profile, but again are rarely needed.
ro
Rh0(D) Immune Globulin (anti-D, WinRho) may be considered in late pregnancy for ITP
in non-splenectomized Rh0(D)+ blood type who do not respond to IV IG or other therapies.
-p
Rh0(D) Immune Globulin will cause maternal hemolysis. thereby excluding patients with a
hemoglobin of <9.0 g/dL [61]. In a small pilot study of pregnant patients with ITP, 6 of 8
re
responded to the initial infusion of anti-D with a platelet count increase of at least 20 x 109/L.
The median increase in platelet counts was 50 x 109/L, but notably 4 of 6 of the responding
lP
patients did require additional therapies for an adequate platelet count for epidural analgesia
and delivery. Treatment with anti-D was associated with a >2.0 gram hemoglobin drop in 1 out
na
of 8 patients [61]. Three of seven newborns in the pilot study developed a positive DAT but this
was not associated with immune hemolytic anemia or jaundice, but larger studies are needed to
ur
establish fetal safety [61]. Pregnant patients who receive anti-D should receive Rho(D) negative
units if transfusion is required [62].
Jo
TPO-R agonists (romiplostim and eltrombopag) [63, 64] are not approved, but have
been used, in pregnant women with refractory ITP late in gestation without reports of serious
adverse events in the fetus [65, 66]. In a single multicenter single-arm study, 74.2% of 32
pregnant ITP patients responded to a TPO–mimetic (rhTPO), now approved for use in China,
without fetal complications [67].
7.7 Delivery: maternal considerations

The mode of delivery can almost always be predicated solely on obstetric indications. Platelets
greater than 20 x 109/L for vaginal and 50 x 109/L for cesarean section are acceptable to
prevent excessive blood loss [68, 69]. However, as noted above, platelets greater than 80 x
109/L are often required for placement of regional analgesia given the theoretical concerns for
Journal Pre-proof
spinal hematoma. The minimal platelet count required to perform neuraxial anesthesia safely
has not been determined. Cesarean delivery should be reserved for routine obstetrical
indications.
7.8 Delivery: neonatal considerations
Although, 10-15% of neonates are born with a platelet count below 150 x 109/L (but see [70] for
higher cited risk), severe thrombocytopenia (platelets <20 x 109) is uncommon and the
incidence of intracerebral hemorrhage is estimated at less than 0.5% [66] [71] [72]. Indeed,
severe thrombocytopenia and intracerebral hemorrhage should prompt consideration of
of
concomitant alloimmune thrombocytopenia or another etiology. The strongest predictor of
neonatal thrombocytopenia is thrombocytopenia in a sibling at birth [72, 73]. Prior splenectomy
ro
does not appear to be predictive [70, 74], successful therapy in the mother is not fully protective,
and there is only a weak correlation between maternal platelet count or therapy at term and
-p
neonatal platelet counts [1]. The presence of circulating maternal antiplatelet antibodies may
re
correlate with the risk of neonatal thrombocytopenia [75] [76], but testing has not found a role in
clinical management to date.
lP
8. Evans Syndrome
na

Evans syndrome is the co-occurrence or sequential development of autoimmune hemolytic
anemia and ITP. The syndrome occurs in approximately 1.8-3.7% of all patients with ITP [46]
ur
[77]. The incidence in pregnancy is not well described but appears rare, and is certainly a far
Jo
less common than a microangiopathic process as a cause of hemolysis (See Section 12)
8.2 Pathogenesis
Evans syndrome is caused by co-existing, but serologically distinct, autoantibodies to platelets
and red blood cells. Almost all patients have a warm-reactive IgG panagglutinin, which causes
extravascular hemolysis due to destruction of the red cells in the spleen [77]. An underlying
disorder will be found in up to 50% of adult patients, most commonly SLE [46].
8.3 Diagnosis
The hemolytic anemia in Evans syndrome is characterized by the finding of spherocytosis on
the peripheral blood smear and a positive direct antiglobulin test (DAT) for IgG and occasionally
Journal Pre-proof
the complement component C3d [77]. Neutropenia also occurs in a small subset of patients,
but has not been reported in pregnancy to date [77].
8.4 Management
The approach to treating Evans syndrome is similar to ITP with prednisone as first-line
intervention. IV IG is far less effective than in isolated ITP, but can be useful in some patients.
In a cohort of 68 non-pregnant patients with Evans syndrome treated with corticosteroids, 83%
had an initial complete response (hemoglobin >12.0 g/dL without biochemical or morphological
markers of hemolysis) or partial response (hemoglobin > 10.0 g/dL and at least 2 g/dL increase
in hemoglobin). However, at mean follow-up of 4 years, 73% were corticosteroid-dependent or
of
required one or more second line therapies (typically splenectomy or rituximab) [46]. Published
ro
experience in pregnancy is limited to case reports and long-term follow-up is lacking. To date,
most reported patients have responded to first-line therapies (steroids with or without IV IG)
-p
and relapse after delivery is infrequent [77]. Red blood cell transfusion may be required for
severe anemia (HgB<7.0 g/dL or a higher threshold in a symptomatic patient), while awaiting
re
response to treatment. Notably, the pan-reacting autoantibody can make cross-matching red
blood cell units for transfusion technically difficult and time consuming. In an unstable patient
lP
with severe anemia, blood bank personal should be alerted to discuss release of “least
incompatible units” if necessary while awaiting a complete work-up[78].
na
Second line therapies for Evans syndrome generally include splenectomy, which has
been reported in one case series to have an initial response of 78% (15 of 19 cases) and a
ur
long-term response of 52% (10 of 19 cases) [46]. As with ITP, splenectomy has been
performed safely in the second trimester in rare, refractory cases [77]. There is little information
Jo
concerning second line therapy for the hemolytic component. Many of the effective treatment in
non-pregnant individuals (danazol and vincristine) are contraindicated in pregnancy [46]. There
are case reports of response to azathioprine, which appears safe in pregnancy [46]. Rituximab
has also been shown to be effective in Evans syndrome, but has risks to the fetus of B-cell
depletion and lymphopenia (see discussion in section 7.6).
There is a risk of the maternal antibodies crossing the placenta and causing hemolysis
or thrombocytopenia in the neonate, but fortunately clinically significant adverse neonatal
outcomes appear to be infrequent. In a review of case reports, 9 of 11 pregnancies resulted in
live births with one report of Coombs-negative hemolysis in the neonate occurring at age 2
months. Two still births were described, one due to intracranial hemorrhage and one neonate
was delivered at 32 weeks with evidence of hemolysis [77].
Journal Pre-proof
9. Hereditary Thrombocytopenia
The hereditary thrombocytopenias comprise a diverse group of disorders that vary in their
phenotype based on the specific gene defect. An estimated incidence of 2.7: 100,000 is
reported in the Italian population [79], but recognition is increasing based on expanded use of
whole exome gene sequencing
9.2 Pathogenesis
Most hereditary thrombocytopenias result from a genetic defect in one of the many steps in
of
megakaryocyte/platelet development (reviewed in [79]). Among the best characterized are the
ro
MYH-9 related (i.e May-Hegglin anomaly, Sebastian syndrome, Fechtner and Epstein
syndromes) and GP1BA GP1BB-related (Bernard Soulier) macrothrombocytopenias.
9.3 Diagnosis
-p
re
A pre-gestational history of thrombocytopenia is helpful, but uncovering a family history of
thrombocytopenia or bleeding/bruising is generally key to raising suspicion. Clinicians should
lP
be aware that such a family history may be lacking in autosomal recessive conditions. Platelet
counts vary from 20-130 x 109/L depending on the specific gene defect. Helpful clues to
na
diagnosis have been the subject of recent review [79]. There are associated physical findings
(e.g. absent radius, albinism) or renal insufficiency that should prompt further consideration of a
ur
syndromic form of congenital thrombocytopenia [79]. In some syndromes, the distinction from
ITP is supported by the finding of “giant” platelets exceeding the size of erythrocytes, a uniform
Jo
population of unusually small platelets [80], or the presence of neutrophil inclusions, but in
others the distinction is not evident by history, physical examination or inspection of the
peripheral blood smear. Platelet counts do not tend to fall precipitously during pregnancy and
bleeding does not suddenly worsen in most patients. When these occur, the diagnosis of ITP or
a pregnancy-specific etiology is more likely.
9.4 Management
The bleeding phenotype generally correlates with the severity of thrombocytopenia unless there
is a superimposed defect in platelet function [79]. The preceding personal and family history of
bleeding is therefore helpful in making decisions regarding management [79]. In the absence of
platelet dysfunction, management decisions are concordant with thresholds for delivery and
Journal Pre-proof
neuraxial anesthesia applied to other disorders. There is little evidence to guide management of
specific inherited platelet function disorders. DDAVP has been used to enhance platelet
function prior to surgeries in such patients. However, the use of DDAVP during pregnancy has
not been well-studied and requires careful management of fluids to limit risk of hyponatremia,
which can be difficult during labor and delivery [81]. Patients with associated platelet
dysfunction, such as in the Bernard Soulier (BS) or gray platelet syndrome, may require platelet
transfusions even if the platelet count exceeds 50 x 109/L [82]. In one retrospective analysis, it
was found that prophylactic platelet transfusions were administered in 46 out of 301 (15.2%)
pregnancies in patients with various platelet function disorders, and were more likely to be given
to patients with BS (28.5% of patients with biallelelic BS). Although there was not a significant
of
difference in post-partum related hemorrhage (defined by hemorrhage requiring blood products)
ro
between patients who did or did not receive prophylactic platelet transfusions, patients with
lower platelet counts were more likely to be transfused [82]. Bleeding tendency, including
-p
outcomes of prior surgical procedures, may help to guide the decision as to whether
prophylactic platelet transfusions should be employed. Patients receiving frequent platelet
re
transfusions during pregnancy should be screened for the presence of HLA antibodies and
HLA-matched platelets should be available for delivery if required. Some patients with BS lack
lP
glycoprotein 1b (GP1b) and thus may also develop platelet-refractoriness due antibodies to
GP1b on transfused platelets [83].
na
10. Antiphospholipid antibody syndrome

ur

Antiphospholipid antibody syndrome (APS) is characterized by arterial and/or venous
Jo
thromboses and/or unexplained recurrent pregnancy loss, stillbirth or early onset and severe
PEC or HELLP. Thrombocytopenia, generally mild to moderate in severity, occurs in 30 to 50%
of affected patients [84]. Approximately 1% of patients present with or develop a catastrophic
and potentially lethal presentation (CAPS) characterized by multi-organ thrombotic
complications [85] that may occur during pregnancy or in the puerperium [86].
10.2 Pathogenesis
The pathophysiology of pregnancy-related morbidity is incompletely understood (see [87] for
review), but includes platelet activation [88] and complement (C3a and C5a) mediated
inflammatory responses within the placenta [89]. Anti-trophoblast antibodies have been
detected in the sera of patients with anticardiolipin antibodies and fetal loss. These antibodies
Journal Pre-proof
may potentially contribute to pathogenesis, but require further study [90]. Thrombosis in APS is
mediated in part by antiphospholipid antibodies that recognize a conformational change in beta-
2-glycoprotein 1 (2GP1) that occurs on the surface of endothelial cells [91], causing
upregulation of E-selection and induction of tissue factor, among other procoagulant responses.
Antiphospholipid antibodies also cause platelet and neutrophil activation, which also likely
contribute to thrombosis [91].
10.3 Diagnosis
Diagnosis is based on the combination of clinical and laboratory features summarized in the
revised Sapporo criteria [92], which include arterial or venous thromboses and the gestational
of
complications listed in table 5. Laboratory criteria are based on recommendations from
ro
International Society of Thrombosis and Hemostasis (ISTH), which includes medium or high
titers of IgG or IgM anticardiolipin antibodies (>40 GPL or >99th percentile) and/or IgG or IgM
-p
anti- β2GP1 antibodies (>99th percentile) and/or a lupus anticoagulant, each measured on two
or more occasions at least 12 weeks apart [29]. The importance of excluding other causes of
re
clinical complications is highlighted by the fact that 1% of the healthy population have
antiphospholipid antibodies by definition, which greatly exceeds the incidence of APS [93]. APS
lP
should also be distinguished from detection of antiphospholipid antibodies per se, which occurs
commonly for example in patients with ITP and does not affect therapeutic decisions other than
na
possibly increasing the risk of maternal thrombosis [94, 95].

Catastrophic APS (CAPS) can present with multiple thromboses (arterial, venous and/or
ur
microvascular), acute multiorgan dysfunction, diffuse alveolar hemorrhage, encephalopathy or

adrenal hemorrhage, among other complications [91]. Diagnosis requires meeting four criteria:
Jo
(1) involvement of three or more organ systems and/or tissues, (2) development of
manifestations simultaneously within one week, (3) laboratory confirmation of antiphospholipid
antibodies, and (4) histopathological confirmation of small vessel occlusion by thrombi [96].
10.4 Management
Women with APS have an increased risk of obstetric complications and lower rates of live births
[97]. APS in pregnancy is a complex topic with many aspects outside the scope of this review.
For the hematologist, it is important to recognize APS as a possible but rare cause of
thrombocytopenia, know the recommendations for treatment and prevention of thrombotic
events, and be able to diagnosis and treat CAPS. Patients with a previous diagnosis APS with
thrombotic events are typically on long-term anticoagulation at the onset of pregnancy.
Journal Pre-proof
Treatment should be switched to therapeutic doses of enoxaparin throughout pregnancy with a

transition back to an oral anticoagulant post-partum [87]. Low-dose aspirin may be added [98].
For patients without a history of thrombosis, the optimal approach to management during
pregnancy has not been well-studied. Some experts guide therapy upon the presence or
absence of past pregnancy-related morbidity. In patients with recurrent pregnancy loss but no
prior thrombotic history, prophylactic dose low-molecular weight heparin and low dose aspirin
during pregnancy and 6 weeks postpartum should be considered. Management of
anticoagulation during pregnancy was subject of a recent comprehensive review in the 2018
ASH Venous Thromboembolism guidelines [99]. ASH guidelines suggest discontinuation of the
anticoagulant 24 hours prior to scheduled delivery [see [99] for details]. There is an ongoing
of
international trial of hydroxychloroquine to prevent obstetrical and thrombotic events in APS
ro
[100]. Treatment of CAPS involves prompt initiation of plasma exchange and therapeutic
anticoagulation, typically with heparin [96]. For progressive or life-threatening complications,
-p
addition of high dose corticosteroids and/or IV IG is recommended [91].
re
11. Type 2B von Willebrand Disease
lP
Von Willebrand Disease (vWD) is the most frequently identified inherited bleeding disorder.
Type 1 vWD, characterized by reduced synthesis or abnormal protein, is most common, but is
na
not associated with thrombocytopenia and type 3 is severe but rare. Type 2 vWD is a
heterogeneous group of disorders characterized impaired synthesis of a dysfunctional von
ur
Willebrand factor (vWF) molecule. Patients with Type 2B vWD have a moderate to moderately
severe bleeding phenotype that may present with thrombocytopenia during pregnancy [101].
Jo
11.2 Pathogenesis
Type 2B vWD is an autosomal dominant disorder caused by a mutation in vWF resulting in
increased affinity for its platelet receptor, glycoprotein 1b. Levels of vWF rise during pregnancy
[102]. In patients with Type 2B vWD, this leads to an increase in binding of the variant vWF to
platelets, which shortens platelet life-span and can lead to moderate or occasionally more
severe thrombocytopenia by the time of delivery [103].
11.3 Diagnosis
The diagnosis should be suspected if there is a pre-gestational personal or a family history of
bleeding (typically epistaxis/menorrhagia or other mucocutaneous bleeding). Evaluation for
Journal Pre-proof
vWD reveals low levels of vWF activity and a ratio of vWF activity to antigen (VWF: RCo/VWF:
Ag) of <0.6 together with loss of high molecular weight vWF multimers. Ristocetin-induced
platelet aggregation (RIPA) or genetic testing is needed to affirm the diagnosis [104].
11.4 Management
vWF antigen, activity (ristocetin cofactor or equivalent), factor VIII levels and platelet counts
should be measured at 32-36 weeks gestation even in the absence of bleeding and as needed
thereafter based on the results. National Heart Lung Blood Institute (NHLBI) vWD guidelines
state that neuraxial anesthesia can be considered for type 1 vWD when VWF:RCo >50%. There
is little data concerning the safety of epidural anesthesia for type 2B patients, and thus this must
of
be a discussion with the patient and anesthesia. If an epidural is placed, it should be removed
ro
as soon as possible following delivery as levels of vWF may fall quickly post-partum [104]. The
criteria for treatment for women having a vaginal delivery is extrapolated from experience with
-p
type 1 vWD. Treatment may not be required for vaginal delivery if vWF Ag, vWF: RCo, and FVIII
are ≥50%. Patients require at least close clinical vigilance and availability of hemostatic agents
re
as patient remain at elevated risk for post-partum hemorrhage. Some experts propose treating
cesarean deliveries as major surgery aiming for a vWF: RCo closer to 80-100% [104] through
lP
replacement with either an intermediate purity plasma-derived factor VIII concentrate (40-60
IU/kg Humate-P or Alphanate) or recombinant VWF (50-80 IU/kg Vonvendi) with maintenance
na
dosing at one-half the initial bolus dose every 8 to 24 hours. Desmopressin (DDAVP) is
generally avoided as it may exacerbate thrombocytopenia. Platelet transfusion to a platelet
ur
count >50 x 109/L is often recommended along with antifibrinolytic therapy (tranexamic acid or
aminocaproic acid) [104, 105]. Patients should be counseled about the substantial risk of
Jo
delayed post-partum hemorrhage over the ensuing 6 weeks. Indeed, some experts suggest that
vWF replacement should be given for 3-7 days postpartum to maintain levels >50% combined
with antifibrinolytic therapy for at least 2-6 weeks [104]. The need for thromboprophylaxis
following cesarean delivery in patients receiving factor replacement is controversial. In patients
undergoing major surgery, thromboprophylaxis appears to be safe if vWF: RCo activity exceeds
50% and FVII: vWF Ag exceeds 50 IU/dL [101].
12. Thrombotic thrombocytopenic purpura

Acquired thrombotic thrombocytopenic purpura (aTTP) is a thrombotic microangiopathy
occurring in 1 in 200,000 pregnancies associated with a severe deficiency of the
Journal Pre-proof
metalloprotease ADAMTS13 that cleaves ultralarge (UL) VWF multimers [1, 106]. An inherited
predisposition to TTP resulting from mutations in ADAMTS13 (Upshaw-Schulman syndrome) is
rare, but may constitute many as a third of all patients who present with TTP during pregnancy
[106]. Indeed, TTP presents for the first time during pregnancy in 25-50% of women with
congenital TTP, but also in 10% of women with acquired TTP [1]. Presentation of a TMA in the
first half of gestation should prompt the diagnosis of TTP to be considered, especially in the
absence of severe renal failure.
12.2 Pathogenesis
Acquired TTP is caused by autoantibodies that inactivate or, less commonly, accelerate the
of
clearance of ADAMTS13 [107]. When ADAMTS13 is inhibited or deficient, there is a failure to
ro
down-regulate the size of UL-VWF multimers released from endothelial cells. UL-VWF
multimers undergoes conformational changes under shear that promote platelet adhesion and
-p
can lead to microvascular occlusion and shearing of red blood cells as they traverse platelet-rich
microthrombi. Placentas from women with uncontrolled congenital and acquired TTP may show
re
widespread placental ischemia and infarcts [108]. Levels of vWF increase in the second or third
trimester in normal pregnancy associated with a decrease in ADAMTS13 [109], which may
lP
predispose to developing clinical manifestations in women with low baseline activity.

na
12.3 Diagnosis
There is overlap in clinical presentation and laboratory values between TTP and pregnancy
ur
specific microangiopathic hemolytic anemias (PEC/HELLP). Thrombocytopenia and hemolytic

anemia are generally more severe and schistocytes and nucleated red blood cells are more
Jo
prevalent on the blood smear in TTP and hypertension and proteinuria are less severe (table 1)
[110]. The indirect bilirubin may be elevated in TTP due to hemolysis, but a significant increase
in transaminase levels would support the diagnosis of HELLP. An ADAMTS13 level of <10%
ADAMTS13 is almost diagnostic in this setting. The diagnosis of congenital TTP may be
suspected based on family history, ADAMTS13 activity of <5%, and the absence of
autoantibody. The diagnosis of congenital TTP is confirmed by genetic testing [107].
12.4 Management
Once the diagnosis of TTP is considered, daily plasma exchange (PLEX) along with
corticosteroids should be initiated as soon as possible while awaiting diagnostic testing. Once
the diagnosis is confirmed, treatment should be continued until clinical stability is accompanied
Journal Pre-proof
by stable recovery of platelet count to >150 x 109/L [111]. The diagnosis of TTP is not an
indication for termination of a viable pregnancy or delivery, depending on the gestational age.
Timely intervention helps protect against severe intrauterine growth restriction and fetal loss,
resulting in live birth rates of ~60-70% [110] [107]. However, the diagnosis of HELLP is an
indication for early delivery. Therefore, it is of critical importance to differentiate between these
two conditions. Rituximab may be reserved for refractory cases. Caplicizumab is an antibody
fragment that binds to vWF that has recently approved by the FDA for the treatment of TTP.
However, there is no published data available as to the use of Caplicizumab in pregnancy and
the drug has the potential, at least in theory, to increase the risk of bleeding in the fetus as well
as in the mother. Patients with suspected congenital TTP should be managed with PLEX as well
of
until the diagnosis is confirmed but can be managed thereafter with regularly scheduled plasma
ro
infusions.
12.5 Counseling for future pregnancies

-p
The counseling and strategy for future pregnancies may differ based on the diagnosis of
re
acquired versus congenital TTP. In the general population, acquired TTP recurs in about 15%
of patients within weeks after clinical remission has been attained and in at least 30-40% of
lP
patients over the subsequent months to years [112]. ADAMTS13 should be monitored at regular
intervals. Levels less than 10% are associated with an increased risk of relapse and should
na
prompt close surveillance and consideration of rituximab, although relapse does not occur in all
such patients [113]. Women who become pregnant again following an episode of acquired TTP
ur
should be monitored closely as recurrent episodes of acquired TTP during pregnancies occurs
in ~10% of patients [114]. ADAMTS13 activity and antibody should be sent prior to or in the first
Jo
trimester to identify patients at high risk for relapse [1]. Fortunately, women with acquired TTP
generally have favorable outcomes if ADAMTS13 are normal at the beginning of pregnancy
[114, 115]. Some experts suggest plasmapheresis for pregnant patients with ADAMTS10 levels
that fall below 5 to 10% even without other clinical/laboratory features of recurrence, but data to
support this practice is limited [107]. An increased incidence of PEC has been reported in
patients who have had a prior episode of acquired TTP [114].
In patients with congenital TTP, the relapse rate is reported at 100% among patients
who do not receive therapy during pregnancy [116]. Prophylactic plasma infusions should be
initiated to maintain ADAMTS13 levels >10% as soon as pregnancy is confirmed [117]. Plasma
infusion (10-15 mg/kg every 2 weeks) has been reported to prevent relapse, although the half-
life of ADAMTS13 is only 2-3 days. An increase in the frequency of plasma infusions may be
Journal Pre-proof
required later in gestation [117]. Platelet counts, LDH, and ADAMTS13 levels should be
followed at regular intervals.
13. Atypical Hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (aHUS) is a TMA with features that overlap with TTP, PEC
and HELLP [37, 118]. aHUS is caused in part by uncontrolled activation of the alternative
complement pathway, often leading to renal failure if untreated. aHUS is a rare disorder,
occurring in 1 out of every 25,000 pregnancies [119]. Ten-20% of patients present for first time
in pregnancy [120]. In one cohort, >75% of pregnancy-associated cases developed in the
of
postpartum period [120].
ro
13.2 Pathogenesis
-p
Most patients have an inherited defect in one or more complement regulatory genes, a gain of
function mutation in C3, or an autoantibody against Factor H, although mutations in other
re
proteins have been reported less frequently (see [37] for review). It has been proposed that
increased complement activation seen during pregnancy overwhelms the marginal control
lP
system in susceptible individuals [37], leading to platelet, neutrophil and endothelial activation
and generation of occlusive platelet thrombi, especially within the microvasculature of the kidney
na
[37].
ur
13.3 Diagnosis
aHUS should be suspected when progressive renal failure (often creatinine > 2 mg/dL) is
Jo
present along with a microangiopathic hemolytic anemia and thrombocytopenia, especially

when there is no response to PLEX. ADAMTS13 levels are >10%. There may be a family
history compatible with the diagnosis. A mutation involving complement is identified in 60-70%
of patients, but the incidence of some of these altered genes in the general population is
uncertain and results are not available in a clinically relevant time-frame.
13.4 Management
Patients in whom there is strong suspicion of aHUS should be treated with the anti-C5
monoclonal antibody, eculizumab [121]. Improvement in thrombocytopenia generally occurs in
48-72 hours, but improvement in renal function and other organ damage can be delayed by
weeks to months. Dosage is 900 mg weekly for the first 4 weeks followed by 1200 mg for the
Journal Pre-proof
fifth dose 1 week later and 1200 mg every 2 weeks thereafter [121]. If eculizumab therapy is
initiated while the patient is undergoing plasmapheresis due to diagnostic uncertainty,
supplemental doses (typically 600 mg) are administered within 60 minutes of exchange [121].
Patients should be vaccinated against meningococcus as soon as possible because of the
induced complement deficiency. Prophylactic antibiotics are administered to patients who have
not been vaccinated within the preceding 2 weeks. Eculizumab is a recombinant IgG molecule
expected to cross the placenta [121], but it has been used safely during pregnancy and in
lactating mothers, primarily for management of paroxysmal nocturnal hemoglobinuria [122, 123].
14. Summary and Future Directions
of
The diagnosis and management of thrombocytopenia in pregnancy requires close attention to
ro
personal and family history, pregestational platelet counts, time of onset, severity and
accompanying clinical and laboratory findings. There are important maternal and fetal
-p
implications that differ depending on etiology. Generally, recommendations regarding mode of
delivery (e.g. vaginal vs. cesarean) are based on obstetric indications. Timely diagnosis and
re
intervention has improved maternal and neonatal outcomes. Occasionally, diagnosis will only
become evident with failure to resolve following delivery.
lP
15. Practice Points

na
- It is important to seek pre-partum platelet counts and other laboratory evaluations and to
interrogate the family history as a guide to the diagnosis of ITP, TTP, aHUS, inherited
ur
thrombocytopenia and type 2b VWD.

- A platelet count <100 x 109/L or thrombocytopenia detected prior to the mid-second trimester
Jo
warrants further investigation and should not be ascribed to gestational thrombocytopenia.

- It is important to review the peripheral blood smear in all patients to exclude signs of MAHA,
such as TTP and aHUS, which demand prompt disease-specific interventions.
- Close coordination between the hematologist and the obstetrician are important to plan the
management of pregnancy and the post-partum period.
16. Research Agenda

- Better understanding of pathogenesis, including genetic disorders of complement regulation,
that may lead to rational interventions or means to forestall PEC and HELLP.
- Studies assessing the safety of TPO-R agonists in pregnancy
- Multicenter studies on the management of TTP/atypical HUS in pregnancy
Journal Pre-proof
- Continued evaluation concerning the safety and efficacy of eculizumab for complement-
mediated disorders during pregnancy
Role of funding source

The funding source has no role in the design or analysis of this review.
Author Contributions
AP and DC selected the literature and designed the review. All authors participated in the
reviewing and editing of the manuscript and approved the final manuscript.
Declaration of Competing Interest
of
AP has received an educational grant from Novo Nordisk Inc. DC has served as a consultant or
advisory board member for Amgen, Rigel, Novartis, Dova, and CSL has received research
ro
support from T2Biosystems, Aplagon, Syntimmune, and Momenta. The other authors have no
conflicts to declare.
Acknowledgements
-p
AP was supported by the 2018 HTRS/Novo Nordisk Clinical Fellowship in Hemophilia and Rare
Bleeding Disorders.
re
lP
na
ur
Jo
Journal Pre-proof
Figures:
Figure 1. Prevalence of causes of thrombocytopenia based on trimester of presentation and
platelet count. The size of each circle represents the relative frequency of all causes of
thrombocytopenia during each of the 3 trimesters of pregnancy. All etiologies and all platelet
counts are considered together in the first trimester when thrombocytopenia is uncommon.
Distribution of etiologies during the second and third trimesters is subdivided by platelet count.
All results are estimates based on personal experience and review of the literature. “Other”
indicates miscellaneous disorders, including infection, DIC, type IIB von Willebrand disease,
immune and nonimmune drug induced thrombocytopenia, paroxysmal nocturnal
hemoglobinuria, bone marrow failure syndromes (aplastic anemia, myelodysplasia,
myeloproliferative disorders, leukemia/ lymphoma, and marrow infiltrative disorders), among
others.
ITP, immune thrombocytopenia; HT, hereditary thrombocytopenia; GT, gestational
thrombocytopenia; HUS, hemolytic uremic syndrome; PEC, preeclampsia/HELLP; TTP,
of
thrombotic thrombocytopenic purpura.
Adapted from Cines DB, Levine LD. Thrombocytopenia in pregnancy. Blood. 2017 Nov
ro
23;130(21):2271-7. with kind permission from the American Society of Hematology
-p
re
lP
na
ur
Jo
Journal Pre-proof
References
[1] Cines DB, Levine LD. Thrombocytopenia in pregnancy. Blood. 2017;130:2271-7.

[2] Reese JA, Peck JD, Deschamps DR, McIntosh JJ, Knudtson EJ, Terrell DR, et al. Platelet
Counts during Pregnancy. N Engl J Med. 2018;379:32-43.
[3] Gernsheimer T, James AH, Stasi R. How I treat thrombocytopenia in pregnancy. Blood.
2013;121:38-47.
[4] Maymon R, Strauss S, Vaknin Z, Weinraub Z, Herman A, Gayer G. Normal sonographic
values of maternal spleen size throughout pregnancy. Ultrasound Med Biol. 2006;32:1827-31.
[5] Practice Bulletin No. 166: Thrombocytopenia in Pregnancy. Obstet Gynecol. 2016;128:e43-
53.
[6] Rottenstreich A, Israeli N, Levin G, Rottenstreich M, Elchalal U, Kalish Y. Clinical
characteristics, neonatal risk and recurrence rate of gestational thrombocytopenia with platelet
count <100 x 10(9)/L. Eur J Obstet Gynecol Reprod Biol. 2018;231:75-9.
of
[7] Kasai J, Aoki S, Kamiya N, Hasegawa Y, Kurasawa K, Takahashi T, et al. Clinical features of
gestational thrombocytopenia difficult to differentiate from immune thrombocytopenia diagnosed
during pregnancy. J Obstet Gynaecol Res. 2015;41:44-9.
ro
[8] Hypertension in pregnancy. Report of the American College of Obstetricians and
Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122:1122-31.
[9] do Prado AD, Piovesan DM, Staub HL, Horta BL. Association of anticardiolipin antibodies
-p
with preeclampsia: a systematic review and meta-analysis. Obstet Gynecol. 2010;116:1433-43.
[10] Burwick RM, Velasquez JA, Valencia CM, Gutierrez-Marin J, Edna-Estrada F, Silva JL, et
re
al. Terminal Complement Activation in Preeclampsia. Obstet Gynecol. 2018;132:1477-85.
[11] Mol BWJ, Roberts CT, Thangaratinam S, Magee LA, de Groot CJM, Hofmeyr GJ. Pre-
eclampsia. Lancet. 2016;387:999-1011.
lP
[12] Phipps E, Prasanna D, Brima W, Jim B. Preeclampsia: Updates in Pathogenesis,

Definitions, and Guidelines. Clin J Am Soc Nephrol. 2016;11:1102-13.
[13] Kohli S, Ranjan S, Hoffmann J, Kashif M, Daniel EA, Al-Dabet MM, et al. Maternal
na
extracellular vesicles and platelets promote preeclampsia via inflammasome activation in

trophoblasts. Blood. 2016;128:2153-64.
[14] Force UPST. Screening for Preeclampsia: US Preventive Services Task Force
Recommendation StatementUSPSTF Recommendation: Screening for PreeclampsiaUSPSTF
ur
Recommendation: Screening for Preeclampsia. JAMA. 2017;317:1661-7.

[15] ACOG Practice Bulletin No. 202: Gestational Hypertension and Preeclampsia. Obstet
Jo
Gynecol. 2019;133:e1-e25.
[16] Redman CW. Hypertension in pregnancy: the NICE guidelines. Heart. 2011;97:1967-9.
[17] Tranquilli AL, Dekker G, Magee L, Roberts J, Sibai BM, Steyn W, et al. The classification,
diagnosis and management of the hypertensive disorders of pregnancy: A revised statement
from the ISSHP. Pregnancy Hypertens. 2014;4:97-104.
[18] Haram K, Mortensen JH, Mastrolia SA, Erez O. Disseminated intravascular coagulation in
the HELLP syndrome: how much do we really know? J Matern Fetal Neonatal Med.
2017;30:779-88.
[19] Bauer AJ, Banek CT, Needham K, Gillham H, Capoccia S, Regal JF, et al. Pravastatin
attenuates hypertension, oxidative stress, and angiogenic imbalance in rat model of placental
ischemia-induced hypertension. Hypertension. 2013;61:1103-10.
[20] Costantine MM, Cleary K, Hebert MF, Ahmed MS, Brown LM, Ren Z, et al. Safety and
pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant
women: a pilot randomized controlled trial. Am J Obstet Gynecol. 2016;214:720.e1-.e17.
[21] Pels A, Kenny LC, Alfirevic Z, Baker PN, von Dadelszen P, Gluud C, et al. STRIDER
(Sildenafil TheRapy in dismal prognosis early onset fetal growth restriction): an international
consortium of randomised placebo-controlled trials. BMC Pregnancy Childbirth. 2017;17:440.
Journal Pre-proof
[22] Phipps EA, Thadhani R, Benzing T, Karumanchi SA. Pre-eclampsia: pathogenesis, novel
diagnostics and therapies. Nat Rev Nephrol. 2019;15:275-89.
[23] Skjaerven R, Wilcox AJ, Lie RT. The interval between pregnancies and the risk of
preeclampsia. N Engl J Med. 2002;346:33-8.
[24] Hernandez-Diaz S, Toh S, Cnattingius S. Risk of pre-eclampsia in first and subsequent
pregnancies: prospective cohort study. BMJ. 2009;338:b2255.
[25] ACOG Committee Opinion No. 743: Low-Dose Aspirin Use During Pregnancy. Obstet
Gynecol. 2018;132:e44-e52.
[26] Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. Antiplatelet agents for prevention of
pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007;369:1791-8.
[27] Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco Matallana C, et al.
Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med.
2017;377:613-22.
[28] Rodger MA, Gris JC, de Vries JIP, Martinelli I, Rey E, Schleussner E, et al. Low-molecular-
of
weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of
individual patient data from randomised controlled trials. Lancet. 2016;388:2629-41.
[29] Devreese KMJ, Ortel TL, Pengo V, de Laat B. Laboratory criteria for antiphospholipid
ro
syndrome: communication from the SSC of the ISTH. J Thromb Haemost. 2018;16:809-13.
[30] Behjat Sasan S, Zandvakili F, Soufizadeh N, Baybordi E. The Effects of Vitamin D
Supplement on Prevention of Recurrence of Preeclampsia in Pregnant Women with a History of
-p
Preeclampsia. Obstet Gynecol Int. 2017;2017:8249264.
[31] Purswani JM, Gala P, Dwarkanath P, Larkin HM, Kurpad A, Mehta S. The role of vitamin D
re
in pre-eclampsia: a systematic review. BMC Pregnancy Childbirth. 2017;17:231.
[32] Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L, Torloni MR. Calcium supplementation during
pregnancy for preventing hypertensive disorders and related problems. Cochrane Database
lP
Syst Rev. 2014:Cd001059.

[33] Fitzpatrick KE, Hinshaw K, Kurinczuk JJ, Knight M. Risk factors, management, and
outcomes of hemolysis, elevated liver enzymes, and low platelets syndrome and elevated liver
na
enzymes, low platelets syndrome. Obstet Gynecol. 2014;123:618-27.

[34] Abildgaard U, Heimdal K. Pathogenesis of the syndrome of hemolysis, elevated liver
enzymes, and low platelet count (HELLP): a review. Eur J Obstet Gynecol Reprod Biol.
2013;166:117-23.
ur
[35] Minakami H, Yamada H, Suzuki S. Gestational thrombocytopenia and pregnancy-induced

antithrombin deficiency: progenitors to the development of the HELLP syndrome and acute fatty
Jo
liver of pregnancy. Semin Thromb Hemost. 2002;28:515-8.

[36] Vaught AJ, Braunstein EM, Jasem J, Yuan X, Makhlin I, Eloundou S, et al. Germline
mutations in the alternative pathway of complement predispose to HELLP syndrome. JCI
Insight. 2018;3.
[37] Merrill SA, Brodsky RA. Complement-driven anemia: more than just paroxysmal nocturnal
hemoglobinuria. Hematology Am Soc Hematol Educ Program. 2018;2018:371-6.
[38] Haram K, Svendsen E, Abildgaard U. The HELLP syndrome: clinical issues and
management. A Review. BMC Pregnancy Childbirth. 2009;9:8.
[39] van Oostwaard MF, Langenveld J, Schuit E, Papatsonis DN, Brown MA, Byaruhanga RN,
et al. Recurrence of hypertensive disorders of pregnancy: an individual patient data
metaanalysis. Am J Obstet Gynecol. 2015;212:624.e1-17.
[40] Liu J, Ghaziani TT, Wolf JL. Acute Fatty Liver Disease of Pregnancy: Updates in
Pathogenesis, Diagnosis, and Management. Am J Gastroenterol. 2017;112:838-46.
[41] Yang Z, Yamada J, Zhao Y, Strauss AW, Ibdah JA. Prospective screening for pediatric
mitochondrial trifunctional protein defects in pregnancies complicated by liver disease. Jama.
2002;288:2163-6.
Journal Pre-proof
[42] Ch'ng CL, Morgan M, Hainsworth I, Kingham JG. Prospective study of liver dysfunction in
pregnancy in Southwest Wales. Gut. 2002;51:876-80.
[43] Minakami H, Morikawa M, Yamada T, Yamada T, Akaishi R, Nishida R. Differentiation of
acute fatty liver of pregnancy from syndrome of hemolysis, elevated liver enzymes and low
platelet counts. J Obstet Gynaecol Res. 2014;40:641-9.
[44] Meng J, Wang S, Gu Y, Lv H, Jiang J, Wang X. Prenatal predictors in postpartum recovery
for acute fatty liver of pregnancy: experiences at a tertiary referral center. Arch Gynecol Obstet.
2016;293:1185-91.
[45] Cines DB, Bussel JB, Liebman HA, Luning Prak ET. The ITP syndrome: pathogenic and
clinical diversity. Blood. 2009;113:6511-21.
[46] Michel M, Chanet V, Dechartres A, Morin AS, Piette JC, Cirasino L, et al. The spectrum of
Evans syndrome in adults: new insight into the disease based on the analysis of 68 cases.
Blood. 2009;114:3167-72.
[47] Kosugi S, Kurata Y, Tomiyama Y, Tahara T, Kato T, Tadokoro S, et al. Circulating
of
thrombopoietin level in chronic immune thrombocytopenic purpura. Br J Haematol.
1996;93:704-6.
[48] Makar RS, Zhukov OS, Sahud MA, Kuter DJ. Thrombopoietin levels in patients with
ro
disorders of platelet production: diagnostic potential and utility in predicting response to TPO
receptor agonists. Am J Hematol. 2013;88:1041-4.
[49] Zhang X, Zhao Y, Li X, Han P, Jing F, Kong Z, et al. Thrombopoietin: a potential diagnostic
-p
indicator of immune thrombocytopenia in pregnancy. Oncotarget. 2016;7:7489-96.
[50] Loustau V, Debouverie O, Canoui-Poitrine F, Baili L, Khellaf M, Touboul C, et al. Effect of
re
pregnancy on the course of immune thrombocytopenia: a retrospective study of 118
pregnancies in 82 women. Br J Haematol. 2014;166:929-35.
[51] Sun D, Shehata N, Ye XY, Gregorovich S, De France B, Arnold DM, et al. Corticosteroids
lP
compared with intravenous immunoglobulin for the treatment of immune thrombocytopenia in

pregnancy. Blood. 2016;128:1329-35.
[52] Rezk M, Masood A, Dawood R, Emara M, El-Sayed H. Improved pregnancy outcome
na
following earlier splenectomy in women with immune thrombocytopenia: a 5-year observational

study. J Matern Fetal Neonatal Med. 2018;31:2436-40.
[53] Marti-Carvajal AJ, Pena-Marti GE, Comunian-Carrasco G. Medical treatments for idiopathic
thrombocytopenic purpura during pregnancy. Cochrane Database Syst Rev. 2009:Cd007722.
ur
[54] Park-Wyllie L, Mazzotta P, Pastuszak A, Moretti ME, Beique L, Hunnisett L, et al. Birth
defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis
Jo
of epidemiological studies. Teratology. 2000;62:385-92.

[55] Yildirim Y, Tinar S, Oner RS, Kaya B, Toz E. Gestational diabetes mellitus in patients
receiving long-term corticosteroid therapy during pregnancy. J Perinat Med. 2006;34:280-4.
[56] Cuker A, Neunert CE. How I treat refractory immune thrombocytopenia. Blood.
2016;128:1547-54.
[57] Chaturvedi S, Arnold DM, McCrae KR. Splenectomy for immune thrombocytopenia: down
but not out. Blood. 2018;131:1172-82.
[58] Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes after maternal
exposure to rituximab. Blood. 2011;117:1499-506.
[59] Gotestam Skorpen C, Hoeltzenbein M, Tincani A, Fischer-Betz R, Elefant E, Chambers C,
et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and
during pregnancy and lactation. Ann Rheum Dis. 2016;75:795-810.
[60] Kamarajah SK, Arntdz K, Bundred J, Gunson B, Haydon G, Thompson F. Outcomes of
Pregnancy in Recipients of Liver Transplants. Clin Gastroenterol Hepatol. 2019;17:1398-
1404.e1.
[61] Michel M, Novoa MV, Bussel JB. Intravenous anti-D as a treatment for immune
thrombocytopenic purpura (ITP) during pregnancy. Br J Haematol. 2003;123:142-6.
Journal Pre-proof
[62] Saol Therapeutics. WinRho SDF [Rho(D) Immune Globulin (Human). U.S. Food and Drug
Administration website. https://www.fda.gov/vaccines-blood-biologics/approved-blood-
products/winrho-sdf-liquid. Accessed October 7 2019.
[63] Wong RSM, Saleh MN, Khelif A, Salama A, Portella MSO, Burgess P, et al. Safety and
efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the
EXTEND study. Blood. 2017;130:2527-36.
[64] Cines DB, Wasser J, Rodeghiero F, Chong BH, Steurer M, Provan D, et al. Safety and
efficacy of romiplostim in splenectomized and nonsplenectomized patients with primary immune
thrombocytopenia. Haematologica. 2017;102:1342-51.
[65] Suzuki N, Hiraga J, Hariyama Y, Takagi Y, Ohashi H, Kishigami Y, et al. A low birth weight
infant with no malformations delivered by a primary immune thrombocytopenia patient treated
with eltrombopag. Int J Hematol. 2018;108:109-11.
[66] Ferreira I, Sousa F, Vasco EM, Areia A, Moura J, Carda J, et al. Severe immune
thrombocytopenia in pregnancy treated with Eltrombopag - A case report. J Gynecol Obstet
of
Hum Reprod. 2018;47:405-8.
[67] Kong Z, Qin P, Xiao S, Zhou H, Li H, Yang R, et al. A novel recombinant human
thrombopoietin therapy for the management of immune thrombocytopenia in pregnancy. Blood.
ro
2017;130:1097-103.
[68] Webert KE, Mittal R, Sigouin C, Heddle NM, Kelton JG. A retrospective 11-year analysis of
obstetric patients with idiopathic thrombocytopenic purpura. Blood. 2003;102:4306-11.
-p
[69] Fujimura K, Harada Y, Fujimoto T, Kuramoto A, Ikeda Y, Akatsuka J, et al. Nationwide
study of idiopathic thrombocytopenic purpura in pregnant women and the clinical influence on
re
neonates. Int J Hematol. 2002;75:426-33.
[70] Karakurt N, Uslu I, Albayrak C, Tomak L, Ozyazici E, Albayrak D, et al. Neonates born to
mothers with immune thrombocytopenia: 11 years experience of a single academic center.
lP
Blood Coagul Fibrinolysis. 2018;29:546-50.

[71] Payne SD, Resnik R, Moore TR, Hedriana HL, Kelly TF. Maternal characteristics and risk of
severe neonatal thrombocytopenia and intracranial hemorrhage in pregnancies complicated by
na
autoimmune thrombocytopenia. Am J Obstet Gynecol. 1997;177:149-55.

[72] Koyama S, Tomimatsu T, Kanagawa T, Kumasawa K, Tsutsui T, Kimura T. Reliable
predictors of neonatal immune thrombocytopenia in pregnant women with idiopathic
thrombocytopenic purpura. Am J Hematol. 2012;87:15-21.
ur
[73] Christiaens GC, Nieuwenhuis HK, Bussel JB. Comparison of platelet counts in first and
second newborns of mothers with immune thrombocytopenic purpura. Obstet Gynecol.
Jo
1997;90:546-52.
[74] Hachisuga K, Hidaka N, Fujita Y, Fukushima K, Kato K. Can we predict neonatal
thrombocytopenia in offspring of women with idiopathic thrombocytopenic purpura? Blood Res.
2014;49:259-64.
[75] Cines DB, Dusak B, Tomaski A, Mennuti M, Schreiber AD. Immune thrombocytopenic
purpura and pregnancy. N Engl J Med. 1982;306:826-31.
[76] Khaspekova SG, Shustova ON, Golubeva NV, Naimushin YA, Larina LE, Mazurov AV.
Circulating antiplatelet antibodies in pregnant women with immune thrombocytopenic purpura
as predictors of thrombocytopenia in the newborns. Platelets. 2019:1-5.
[77] Lefkou E, Nelson-Piercy C, Hunt BJ. Evans' syndrome in pregnancy: a systematic literature
review and two new cases. Eur J Obstet Gynecol Reprod Biol. 2010;149:10-7.
[78] Lechner K, Jager U. How I treat autoimmune hemolytic anemias in adults. Blood.
2010;116:1831-8.
[79] Noris P, Pecci A. Hereditary thrombocytopenias: a growing list of disorders. Hematology
Am Soc Hematol Educ Program. 2017;2017:385-99.
Journal Pre-proof
[80] Bolton-Maggs PHB, Chalmers EA, Collins PW, Harrison P, Kitchen S, Liesner RJ, et al. A
review of inherited platelet disorders with guidelines for their management on behalf of the
UKHCDO. Br J Haematol. 2006;135:603-33.
[81] Coppola A, Di Minno G. Desmopressin in inherited disorders of platelet function.
Haemophilia. 2008;14 Suppl 1:31-9.
[82] Noris P, Schlegel N, Klersy C, Heller PG, Civaschi E, Pujol-Moix N, et al. Analysis of 339
pregnancies in 181 women with 13 different forms of inherited thrombocytopenia.
Haematologica. 2014;99:1387-94.
[83] Gernsheimer TB. Congenital and acquired bleeding disorders in pregnancy. Hematology
Am Soc Hematol Educ Program. 2016;2016:232-5.
[84] Comellas-Kirkerup L, Hernandez-Molina G, Cabral AR. Antiphospholipid-associated
thrombocytopenia or autoimmune hemolytic anemia in patients with or without definite primary
antiphospholipid syndrome according to the Sapporo revised classification criteria: a 6-year
follow-up study. Blood. 2010;116:3058-63.
of
[85] Cervera R, Serrano R, Pons-Estel GJ, Ceberio-Hualde L, Shoenfeld Y, de Ramon E, et al.
Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre
prospective study of 1000 patients. Ann Rheum Dis. 2015;74:1011-8.
ro
[86] Gomez-Puerta JA, Cervera R, Espinosa G, Asherson RA, Garcia-Carrasco M, da Costa IP,
et al. Catastrophic antiphospholipid syndrome during pregnancy and puerperium: maternal and
fetal characteristics of 15 cases. Ann Rheum Dis. 2007;66:740-6.
-p
[87] Chaturvedi S, McCrae KR. Diagnosis and management of the antiphospholipid syndrome.
Blood Rev. 2017;31:406-17.
re
[88] McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anti-phospholipid antibodies are
directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-
glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A. 1990;87:4120-4.
lP
[89] Salmon JE, Girardi G, Holers VM. Activation of complement mediates antiphospholipid
antibody-induced pregnancy loss. Lupus. 2003;12:535-8.
[90] McCrae KR, DeMichele AM, Pandhi P, Balsai MJ, Samuels P, Graham C, et al. Detection
na
of antitrophoblast antibodies in the sera of patients with anticardiolipin antibodies and fetal loss.
Blood. 1993;82:2730-41.
[91] Garcia D, Erkan D. Diagnosis and Management of the Antiphospholipid Syndrome. N Engl
J Med. 2018;379:1290.
ur
[92] Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International
consensus statement on an update of the classification criteria for definite antiphospholipid
Jo
syndrome (APS). J Thromb Haemost. 2006;4:295-306.

[93] Shi W, Krilis SA, Chong BH, Gordon S, Chesterman CN. Prevalence of lupus anticoagulant
and anticardiolipin antibodies in a healthy population. Aust N Z J Med. 1990;20:231-6.
[94] Frison L, Lombardi A, Caputo I, Semenzato G, Fabris F, Vianello F. Relevance of
antiphospholipid antibody profile in the clinical outcome of ITP: a single-centre study.
Hematology. 2019;24:134-8.
[95] Le Guenno G, Guieze R, Audia S, Khellaf M, Michel M, Bonnotte B, et al. Characteristics,
risk factors and management of venous thromboembolism in immune thrombocytopenia: a
retrospective multicenter study. Intern Med J. 2019.
[96] Asherson RA, Cervera R, de Groot PG, Erkan D, Boffa MC, Piette JC, et al. Catastrophic
antiphospholipid syndrome: international consensus statement on classification criteria and
treatment guidelines. Lupus. 2003;12:530-4.
[97] Saccone G, Berghella V, Maruotti GM, Ghi T, Rizzo G, Simonazzi G, et al. Antiphospholipid
antibody profile based obstetric outcomes of primary antiphospholipid syndrome: the
PREGNANTS study. Am J Obstet Gynecol. 2017;216:525.e1-.e12.
[98] Practice Bulletin No. 132: Antiphospholipid syndrome. Obstet Gynecol. 2012;120:1514-21.
Journal Pre-proof
[99] Bates SM, Rajasekhar A, Middeldorp S, McLintock C, Rodger MA, James AH, et al.
American Society of Hematology 2018 guidelines for management of venous thromboembolism:
venous thromboembolism in the context of pregnancy. Blood Adv. 2018;2:3317-59.
[100] Belizna C, Pregnolato F, Abad S, Alijotas-Reig J, Amital H, Amoura Z, et al. HIBISCUS:
Hydroxychloroquine for the secondary prevention of thrombotic and obstetrical events in primary
antiphospholipid syndrome. Autoimmun Rev. 2018;17:1153-68.
[101] Tosetto A, Castaman G. How I treat type 2 variant forms of von Willebrand disease. Blood.
2015;125:907-14.
[102] Drury-Stewart DN, Lannert KW, Chung DW, Teramura GT, Zimring JC, Konkle BA, et al.
Complex changes in von Willebrand factor-associated parameters are acquired during
uncomplicated pregnancy. PLoS One. 2014;9:e112935.
[103] Ranger A, Manning RA, Lyall H, Laffan MA, Millar CM. Pregnancy in type 2B VWD: a case
series. Haemophilia. 2012;18:406-12.
[104] Kruse-Jarres R, Johnsen JM. How I treat type 2B von Willebrand disease. Blood.
of
2018;131:1292-300.
[105] Kouides PA. Antifibrinolytic therapy for preventing VWD-related postpartum hemorrhage:
indications and limitations. Blood Adv. 2017;1:699-702.
ro
[106] Mariotte E, Azoulay E, Galicier L, Rondeau E, Zouiti F, Boisseau P, et al. Epidemiology
and pathophysiology of adulthood-onset thrombotic microangiopathy with severe ADAMTS13
deficiency (thrombotic thrombocytopenic purpura): a cross-sectional analysis of the French
-p
national registry for thrombotic microangiopathy. Lancet Haematol. 2016;3:e237-45.
[107] Scully M, Thomas M, Underwood M, Watson H, Langley K, Camilleri RS, et al. Thrombotic
re
thrombocytopenic purpura and pregnancy: presentation, management, and subsequent
pregnancy outcomes. Blood. 2014;124:211-9.
[108] Crawley JT, Scully MA. Thrombotic thrombocytopenic purpura: basic pathophysiology and
lP
therapeutic strategies. Hematology Am Soc Hematol Educ Program. 2013;2013:292-9.

[109] Sanchez-Luceros A, Farias CE, Amaral MM, Kempfer AC, Votta R, Marchese C, et al. von
Willebrand factor-cleaving protease (ADAMTS13) activity in normal non-pregnant women,
na
pregnant and post-delivery women. Thromb Haemost. 2004;92:1320-6.

[110] Thomas MR, Robinson S, Scully MA. How we manage thrombotic microangiopathies in
pregnancy. Br J Haematol. 2016;173:821-30.
[111] George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood.
ur
2010;116:4060-9.
[112] Kremer Hovinga JA, Vesely SK, Terrell DR, Lammle B, George JN. Survival and relapse
Jo
in patients with thrombotic thrombocytopenic purpura. Blood. 2010;115:1500-11; quiz 662.

[113] George JN. TTP: long-term outcomes following recovery. Hematology Am Soc Hematol
Educ Program. 2018;2018:548-52.
[114] Jiang Y, McIntosh JJ, Reese JA, Deford CC, Kremer Hovinga JA, Lammle B, et al.
Pregnancy outcomes following recovery from acquired thrombotic thrombocytopenic purpura.
Blood. 2014;123:1674-80.
[115] Scully M. Thrombotic Thrombocytopenic Purpura and Atypical Hemolytic Uremic
Syndrome Microangiopathy in Pregnancy. Semin Thromb Hemost. 2016;42:774-9.
[116] Moatti-Cohen M, Garrec C, Wolf M, Boisseau P, Galicier L, Azoulay E, et al. Unexpected
frequency of Upshaw-Schulman syndrome in pregnancy-onset thrombotic thrombocytopenic
purpura. Blood. 2012;119:5888-97.
[117] Epperla N, Hemauer K, Friedman KD, George JN, Foy P. Congenital thrombotic
thrombocytopenic purpura related to a novel mutation in ADAMTS13 gene and management
during pregnancy. Am J Hematol. 2016;91:644-6.
[118] Jokiranta TS. HUS and atypical HUS. Blood. 2017;129:2847-56.
Journal Pre-proof
[119] Gaggl M, Aigner C, Csuka D, Szilagyi A, Prohaszka Z, Kain R, et al. Maternal and Fetal
Outcomes of Pregnancies in Women with Atypical Hemolytic Uremic Syndrome. J Am Soc
Nephrol. 2018;29:1020-9.
[120] Fakhouri F, Roumenina L, Provot F, Sallee M, Caillard S, Couzi L, et al. Pregnancy-
associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am
Soc Nephrol. 2010;21:859-67.
[121] Soliris (eculizumab). Package Insert. 2007.
[122] Mussoni MP, Veneziano FA, Boetti L, Tassi C, Calisesi C, Nucci S, et al. Innovative
therapeutic approach: sequential treatment with plasma exchange and eculizumab in a
pregnant woman affected by atypical hemolytic-uremic syndrome. Transfus Apher Sci.
2014;51:134-6.
[123] Sarno L, Tufano A, Maruotti GM, Martinelli P, Balletta MM, Russo D. Eculizumab in
pregnancy: a narrative overview. J Nephrol. 2019;32:17-25.
of
ro
-p
re
lP
na
ur
Jo
Journal Pre-proof
Table 1. Prevalence of laboratory abnormalities by etiology of thrombocytopenia
G ITP HT TTP aHUS Type PEC HELLP AFLP APS

T IIBV
WD
Complet ≥7 Any, 20- <100 20-150 <50, >50 ( 50-100 >50 ≥50
e Blood 5 varia 130 variab <50 in
CountPl ble le <5% of
atelet (x women)
9
10 /L)
Hemoglo
bin
— — —
↓↓ ↓↓ —
—/ ↓ —/ ↓ — —
of
Peripher — ± ± +++schisto +++schist — ±schisto ±schisto — ±schistocyte
al Smear Few Giant cytes ocytes cytes cytes s
large platel
ro
platel ets or
ets small
platel
ets±
WBC
inclusi
-p
re
ons
LDH — — — ↑/↑↑↑ ↑/↑↑ — ↑ ↑↑ ↑↑ —
lP
↑
Creatini — — — —/↑ ↑↑↑ — —/↑ — /↑ — —/↑
ne /↑
na
Liver — — — —/ ↑ —/↑ — — ↑↑↑ ↑↑ —/↑

function ↑
testsAST
ur
/ALT
Tbili — —— —— ↑↑ ↑↑ —— —/↑— ↑↑ ↑↑ ——
Indirect — — — ↑↑ ↑
Jo
Direct
PT — — — — — —/↑ — ↑ ↑↑ —/↑
and/or
PTT
Urine — — — — ↑ — ↑ ↑ ↑
—/↑
Protein
Other — — — ADAMTS1 ADAMTS1 vWF — — Elevat Antibodies
Laborato 3≤10% 3 >10% RCo/v ed tocardiolipin
ry WF Ag amm and/or 2
features <0.6, onia glycoprotein
loss of Low and/or lupus
HMW blood anticoagula
multi gluco nt
mers se
Journal Pre-proof
↑, elevated laboratory value prevalent feature; ↓, decreased laboratory value prevalent feature; —,
abnormality of laboratory feature not usually present. Number of arrows indicates estimated prevalence of
laboratory feature based on literature and clinical experience. Reference ranges in healthy pregnancy
must be taken into consideration
GT, gestational thrombocytopenia; ITP, immune thrombocytopenia; HT, hereditary thrombocytopenia;
TTP, thrombotic thrombocytopenia purpura; HUS, Hemolytic Uremic Syndrome; Type II VWD, Type II
von willebrand disease; PC, preeclampsia; HELLP, hemolysis elevated liver enzymes low platelet count
syndrome; AFLP, acute fatty liver of pregnancy,; APS, antiphospholipid syndrome; ALT, alanine
,
aminotransferase; AST aspartate aminotransferase; PT, prothrombin time; PTT, partial thromboplastin
time; LDH, lactate dehydrogenase
Adapted from Gernsheimer T, James AH, Stasi R. How I treat thrombocytopenia in pregnancy. Blood
2013;121:38-47 and Cines DB, Levine LD. Thrombocytopenia in pregnancy. Blood 2017;130:2271-2277.
of
ro
-p
re
lP
na
ur
Jo
Journal Pre-proof
Table 2. High risk features for developing pre-eclampsia

High Risk
History of preeclampsia Renal Disease Type 2 diabetes
Multifetal Gestation Autoimmune disease Chronic Hypertension
Moderate Risk
First pregnancy Maternal Age ≥35 BMI ≥30
Family history of preeclampsia Sociodemographic Personal History Factors
characteristics
Adapted with permission from LeFevre et al Low-Dose Aspirin Use for the Prevention of
Morbidity and Mortality From Preeclampsia: U.S. Preventive Services Task Force
of
Recommendation Statement**
ro
Table 3. Swansea criteria for acute fatty liver of pregnancy
Swansea criteria1
-p
Patient positive for at least 6 out of 15 of the following criteria:
Vomiting
re
Elevated urea 950mg/dL
Abdominal pain
Polydipsia/polyuria
lP
Encephalopathy
Bilirubin >0.8 mg/dL
Hypoglycemia <72 mg/dL
Coagulopathy or PT >14 seconds
na
Acute kidney injury or Cr >1.7 mg/dL

“Bright liver” on ultrasound
Ammonia >66 µmol/L
ALT >42 U/L
ur
Ascites
WBC >11 x 10 9 /L
Microvascular steatosis on liver biopsy
Jo
1
Ch'ng CL, Morgan M, Hainsworth I, et al. Prospective study of liver dysfunction in pregnancy
in Southwest Wales. Gut 2002;51:876-880
Journal Pre-proof
Table 4. Therapies for Immune Thrombocytopenia in Pregnancy

Dosing Pregnancy-specific notes
First Line
a
Prednisone 0.25-1mg/kg prednisone Maternal- Increased risk for
gestational diabetes, mood
lability,
Fetal- increased risk of cleft
palate in early pregnancy
IV IG 0.5 g/kg-1 g/kg IV Maternal- Thrombotic risk in
general population studies
b
Second Line
Splenectomy n/a Maternal- Safety reported up to
of
the second trimester. Impaired
future immune response to
encapsulated organisms,
ro
requires vaccinations to
decrease risk
Azathioprine 1-2 mg/kg PO once per day Maternal- Reports of use in
Cyclosporine
(maximum 150mg/d)
-p
5-6 mg/kg/d PO divided into 2 doses
rheumatologic/transplant
indications in pregnancy
Maternal- Reports of use in
re
(titrate to blood levels of 100-200 rheumatologic/transplant
ng/mL) indications in pregnancy
Rituximab 375 mg/m2 IV once per week x 4 Maternal- Increased
lP
weeks susceptibility to viral infections,

reactivation of hepatitis B
infection
Fetal-Risk to neonate of B-cell
na
lymphopenia
TPO-R agonists Maternal/fetal- Further studies
Romiplostim 1-10 mcg/kg subq weekly needed. Case reports of use in
ur
Eltrombopag 25-75 mg PO daily pregnancy without known

adverse events
Rho(D) Immune Globulin HgB ≥10g/dL: 50 mcg as a single Maternal- Risk of severe
Jo
injection or separate days intravascular hemolysis

HgB 8 to <10 g/dL: 25 to 40 mcg as (maternal)
a single injection, or can be given as Fetal- possible autoimmune
2 divided doses on separate days. hemolysis
HgB <8g/dL: Use not recommended
a
Typical dosing for ITP 1 mg/kg, some experts suggest trialing lower doses in pregnancy
b
Inadequate data to support an order to second-line approach
Journal Pre-proof
Table 5. Revised Sappora Criteria for Antiphospholipid Antibody syndrome - Clinical and
Pregnancy morbidity
Clinical Criteria Pregnancy morbidity

One or more clinical episodes of arterial, venous One or more unexplained deaths of a
th
or small vessel thrombosis, in any tissue or organ. morphologically normal fetus at or beyond the 10
Thrombosis must be confirmed using imaging or week of gestation
Doppler or histopathology One or more premature births (<34 weeks of
gestation) of a morphologically normal neonate,
because of eclampsia, severe pre-eclampsia and
placental insufficiency
Three or more unexplained consecutive
th
spontaneous abortions before the 10 week of
of
gestation (excluded maternal anatomic or
hormonal abnormalities and chromosomal cause)
ro
Adapted with permission from Miyakis S, Lockshin MD, Atsumi T, et al. International consensus
statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). Journal
of thrombosis and haemostasis : JTH 2006;4:295-306
-p
re
lP
na
ur
Jo
Figure 1

10 1016@j Blre 2019 100638 PDF

Hochgeladen von

Dokumentinformationen

Originaltitel

Copyright

Verfügbare Formate

Dieses Dokument teilen

Dokument teilen oder einbetten

Freigabeoptionen

Stufen Sie dieses Dokument als nützlich ein?

Sind diese Inhalte unangemessen?

Copyright:

Verfügbare Formate

10 1016@j Blre 2019 100638 PDF

Hochgeladen von

Copyright:

Verfügbare Formate

Journal Pre-proof

Thrombocytopenia in pregnancy: Diagnosis and approach to

Allyson M. Pishko, Lisa D. Levine, Douglas B. Cines

To appear in: Blood Reviews

© 2019 Published by Elsevier.

Thrombocytopenia in Pregnancy: Diagnosis and Approach to Management

2. General Approach to Evaluation of Thrombocytopenia in Pregnancy

The differential diagnosis of thrombocytopenia in pregnancy is impacted by the time of

suggesting infection or multi-system disease, family history suggestive of an inherited

2.2 Etiologies by Trimester

2.3 Laboratory Testing

diagnosis of thrombocytopenia in pregnancy is outlined in table 1.

other serious complications during subsequent pregnancies.

severe PEC [8].

to improve by 48-72 hours after delivery should prompt consideration of an alternative

4.5 Counseling for future pregnancies

5. Hemolysis, elevated liver enzymes, low platelets syndrome

Urgent delivery is the cornerstone of management. Management of maternal hypertension and

6. Acute fatty liver of pregnancy

Diagnosis of ITP is based on the constellation of isolated thrombocytopenia, an otherwise

7.4 Maternal considerations prior to gestation

generally considered to be safe in pregnancy. However, high-dose corticosteroid therapy are

7.6 Management during gestation-Second line therapies

7.7 Delivery: maternal considerations

7.8 Delivery: neonatal considerations

8.1 Definition and Incidence

10. Antiphospholipid antibody syndrome

10.1 Definition and Incidence

possibly increasing the risk of maternal thrombosis [94, 95].

microvascular), acute multiorgan dysfunction, diffuse alveolar hemorrhage, encephalopathy or

Treatment should be switched to therapeutic doses of enoxaparin throughout pregnancy with a

12. Thrombotic thrombocytopenic purpura

predispose to developing clinical manifestations in women with low baseline activity.

specific microangiopathic hemolytic anemias (PEC/HELLP). Thrombocytopenia and hemolytic

12.5 Counseling for future pregnancies

13. Atypical Hemolytic uremic syndrome

present along with a microangiopathic hemolytic anemia and thrombocytopenia, especially

14. Summary and Future Directions

15. Practice Points

thrombocytopenia and type 2b VWD.

warrants further investigation and should not be ascribed to gestational thrombocytopenia.

16. Research Agenda

Role of funding source

Declaration of Competing Interest

[1] Cines DB, Levine LD. Thrombocytopenia in pregnancy. Blood. 2017;130:2271-7.

[12] Phipps E, Prasanna D, Brima W, Jim B. Preeclampsia: Updates in Pathogenesis,

extracellular vesicles and platelets promote preeclampsia via inflammasome activation in

Recommendation: Screening for Preeclampsia. JAMA. 2017;317:1661-7.

Syst Rev. 2014:Cd001059.

enzymes, low platelets syndrome. Obstet Gynecol. 2014;123:618-27.

[35] Minakami H, Yamada H, Suzuki S. Gestational thrombocytopenia and pregnancy-induced

liver of pregnancy. Semin Thromb Hemost. 2002;28:515-8.

compared with intravenous immunoglobulin for the treatment of immune thrombocytopenia in

following earlier splenectomy in women with immune thrombocytopenia: a 5-year observational

of epidemiological studies. Teratology. 2000;62:385-92.

Blood Coagul Fibrinolysis. 2018;29:546-50.

autoimmune thrombocytopenia. Am J Obstet Gynecol. 1997;177:149-55.

syndrome (APS). J Thromb Haemost. 2006;4:295-306.

therapeutic strategies. Hematology Am Soc Hematol Educ Program. 2013;2013:292-9.

pregnant and post-delivery women. Thromb Haemost. 2004;92:1320-6.

in patients with thrombotic thrombocytopenic purpura. Blood. 2010;115:1500-11; quiz 662.

Table 1. Prevalence of laboratory abnormalities by etiology of thrombocytopenia

G ITP HT TTP aHUS Type PEC HELLP AFLP APS