CID Y HPP, JUNIO 2023.pdf

Maternal Coagulation
Disorders and
Postpartum
Hemorrhage
TRACY C. BANK, MD,* MARWAN MA’AYEH, MD,†
and KARA M. ROOD, MD*
*Department of Obstetrics & Gynecology, The Ohio State University
Wexner Medical Center, Columbus, Ohio; and †Department of
Obstetrics & Gynecology, ChristianaCare, Newark, Delaware
Abstract: Coagulation disorders are rare causes of
postpartum hemorrhage. Disturbances in coagulation
should be suspected in patients with a family history of
coagulopathy, those with a personal history of heavy
menstrual bleeding, and those with persistent bleeding
despite correction of other causes. The coagulopathic
conditions discussed include disseminated intravascu-
lar coagulation, platelet disorders, and disturbances of
coagulation factors. These should not be overlooked
in the evaluation of obstetric hemorrhage, as diagnosis
and appropriate treatment may prevent severe mater-
nal morbidity and mortality.
Key words: coagulopathy, postpartum hemorrhage,
thrombocytopenia, disseminated intravascular coag-
ulation, severe maternal morbidity
Introduction
Disorders of coagulation are some of the
less common causes of postpartum hem-
orrhage. Coagulation disturbances should
be suspected in patients with a family
history of coagulopathy and in those with
a personal history of heavy menstrual
bleeding. Clinical circumstances may also
suggest coagulation defects as a cause of
postpartum hemorrhage. Coagulopathy
should be suspected in a patient with
hemorrhage who has no evidence of
uterine atony, significant lacerations, re-
tained placenta, or other identifiable di-
rect cause. In addition, it should be
considered when heavy bleeding persists
despite correction of other causes.
The coagulation disorders discussed
are divided into 3 categories: dissemi-
nated intravascular coagulation (DIC),
platelet disorders, and disturbances of
coagulation factors.
DIC
DIC is a syndrome characterized by
diffuse activation of the coagulation
system leading to intravascular fibrin
deposition.1
This massive activation of
The authors declare that they have nothing to disclose.
Correspondence: Tracy C. Bank, MD, 395 W. 12th
Avenue, 5th Floor, Columbus, OH. E-mail: tracycar
oline46@gmail.com
CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 66 / NUMBER 2 / JUNE 2023
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CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 66, Number 2, 384–398
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Copyright r 2023 Wolters Kluwer Health, Inc. All rights reserved.

coagulation results in the depletion of
coagulation factors and platelets (con-
sumptive coagulopathy) and leads to
hemorrhagic complications. Clinically
evident DIC is rare, complicating 0.03%
to 0.35% of pregnancies.2
However, when
present, it can be a source of significant
morbidity and mortality; it is identified as
a contributing factor in up to 25% of
maternal deaths.3
Many patients with
DIC have an underlying obstetric
complication, commonly massive hemor-
rhage, placental abruption, sepsis, pree-
clampsia, and, less commonly, prolonged
intrauterine fetal demise or amniotic fluid
embolism.1,4,5
Recent data have also sug-
gested that maternal COVID-19 infection
is associated with an increased risk of
DIC.2
Activation of the coagulation system is
mediated by proinflammatory cytokines
produced by leukocytes and endothelial
cells.1
The result triggers the tissue factor/
factor VIIa pathway, traditionally de-
scribed as the extrinsic clotting cascade,
resulting in the depletion of platelets,
fibrinogen, prothrombin, and factors V
and VIII. The usual inhibitory systems of
protein C, S, and antithrombin III are
depressed. Intravascular fibrin deposition
occurs and is enhanced by high circulat-
ing levels of plasminogen activator inhib-
itor-1.4
As fibrinolysis occurs, fibrin
degradation products further interfere
with the coagulation cascade.
DIC is also associated with thrombotic
complications, as small clots are formed
in the microcirculation causing ischemia.
Therefore, patients can present with neu-
rological manifestations, skin ischemia or
superficial gangrene, renal cortical ne-
crosis, and uremia due to thrombosis.
Fibrinogen degradation products can also
directly damage the endothelial lining of
pulmonary capillary beds leading to acute
lung injury, and the surface of red blood
cells leading to hemolysis.6
Although no specific biomarkers for
DIC exist, the laboratory diagnosis
of DIC is relatively straightforward
(Fig. 1). The platelet count is invariably
decreased or drops progressively. Fibri-
nogen levels are low, usually <200 mg/
dL.7
Fibrin degradation products are
elevated. The prothrombin time (PT)
and partial thromboplastin time (PTT)
may be normal or prolonged; normal
levels are usually seen early in the course
FIGURE 1. Evaluation of coagulation disturbance in acute hemorrhage. DIC indicates dis-
seminated intravascular coagulation; FFP, fresh-frozen plasma; PT, prothrombin time; PTT,
partial thromboplastin time.
Maternal Coagulation Disorders 385
www.clinicalobgyn.com

of the syndrome, before significant deple-
tion of coagulation factors and an
increase in fibrin degradation occurs.
Approximately 15% of DIC cases are
associated with laboratory signs of he-
molysis, including low hemoglobin, ele-
vated lactate dehydrogenase, and elevated
total bilirubin.8
Treatment of DIC relies on recognition
and management of the inciting condi-
tion. Additional therapy includes replet-
ing blood volume and correcting
hypotension and hypoxia. In addition,
recent literature has focused on the rec-
ognition of nonovert DIC, characterized
by subtle hemostatic dysfunction without,
or occurring before, decompensation,
with an emphasis on identifying and
halting the DIC process before it becomes
clinically evident.2
PLATELET DISORDERS
Thrombocytopenia is the most common
platelet disorder encountered in preg-
nancy. The most common cause of
thrombocytopenia in pregnancy is gesta-
tional thrombocytopenia, which accounts
for ~70% of cases. Gestational thrombo-
cytopenia is generally mild, with platelet
counts typically > 70,000/μL.9,10
This con-
dition is not associated with an increased
risk of maternal hemorrhagic complica-
tions. There is, however, a low but existing
risk of neonatal thrombocytopenia associ-
ated with severe gestational thrombocyto-
penia, especially when platelet counts drop
below 100,000/μL.11
Other common causes of thrombocyto-
penia in pregnancy are preeclampsia with
severe features; hemolysis, elevated liver
function tests, low platelets (HELLP)
syndrome; and immune thrombocyto-
penic purpura (ITP). Rare causes include
DIC, thrombotic thrombocytopenic pur-
pura (TTP), hemolytic uremic syndrome
(HUS), other immune thrombocytope-
nias, drug-induced thrombocytopenia,
and hereditary thrombocytopenia. The
initial recommended evaluations are
reviewed in Figure 2.
FIGURE 2. Screening for suspected coagulation disturbance. DIC indicates disseminated in-
travascular coagulation; FFP, fresh-frozen plasma; HELLP, hemolysis, elevated liver function
tests, low platelets; HUS, hemolytic uremic syndrome; ITP, immune thrombocytopenic purpura;
PT, prothrombin time; PTT, partial thromboplastin time; TTP, thrombotic thrombocytopenic
purpura; vWD, Von Willebrand Disease; VWF, von Willebrand factor; vWF:Ag, vWF:antigen,
vWF:Rco, vWF:ristocetin cofactor.
386 Bank et al

Functional platelet disorders are rare
but may contribute to significant hemor-
rhagic complications. The majority of
these disorders are inherited, although
family history is not always predictive.
Many of these patients will be diagnosed
prepregnancy because of bleeding com-
plications in childhood; however, the
hemostatic challenge of delivery may un-
cover previously unidentified platelet
dysfunction.
ITP
ITP affects 1 in 1000 pregnancies and
accounts for 5% of pregnancy-associated
thrombocytopenias.12
The pathophysiol-
ogy of ITP involves the production of
antibodies to platelet glycoproteins and
other determinants, resulting in the coat-
ing of platelets with IgG antibodies.
These platelets are then cleared from the
circulation by tissue macrophages, pre-
dominantly in the spleen. Platelet produc-
tion may be impaired by megakaryocytic
damage in these patients as well, further
contributing to thrombocytopenia.13
The diagnosis of ITP is one of exclu-
sion. A complete blood count should be
normal with the exception of thrombocy-
topenia; however, anemia would also be
expected if ITP is discovered after an
event involving acute blood loss. While
gestational thrombocytopenia typically
presents later in pregnancy and resolves
by 12 weeks postpartum, ITP can develop
at any time from preconception through-
out pregnancy, and can persist postpar-
tum. ITP is also typically more severe,
with platelet counts <100,000/μL.14
A
peripheral smear should also be normal
with the exception of fewer platelets and
the presence of somewhat larger, imma-
ture platelets.15
For most patients of
reproductive age, a bone marrow aspirate
is unnecessary for diagnosis, but may be
helpful in atypical cases or patients who
do not respond to usual therapy. Meas-
urement of platelet-associated antibodies
is generally not diagnostic, with a sensi-
tivity of 49% to 66%. The test is also not
specific for ITP, as those with gestational
thrombocytopenia can also have platelet-
associated antibodies.16
Treatment of ITP during pregnancy is
indicated when platelet counts fall below
30,000/μL.17
Near term, many authorities
advocate therapy to raise the platelet
count to 50,000/μL or more. Outside of
pregnancy, a lower threshold (20 to
30,000/μL) may be considered; however,
bleeding is expected at the time of deliv-
ery, especially if a cesarean becomes
indicated, and thus optimization is rec-
ommended before the anticipated time of
delivery to minimize the risk of peripar-
tum hemorrhage.18
Corticosteroids are
the first line of treatment for ITP, with
response rates during pregnancy of over
50% to 60%.19
A response is usually seen
within 1 week of initiating therapy, with a
maximum response in 2 to 3 weeks. Intra-
venous immune globulin is generally used
as a second-line agent for individuals who
are steroid nonresponsive. A dose of 1 g/
kg/d for 2 to 3 days typically results in an
improvement in platelet count within
7 days.20
Anti-D immunoglobulin is
an alternative treatment which can be
used in Rh-positive patients. Limited data
TABLE 1. Swansea Criteria for Acute Fatty
Liver of Pregnancy (AFLP)35
For diagnosis, must have 6 or more of the
following, without an alternative etiology
identified:
Vomiting
Abdominal pain
Polydipsia/polyuria
Encephalopathy
Elevated bilirubin
Hypoglycemia
Elevated urate
Leukocytosis
Ascites or bright liver on ultrasound
Transaminitis
Elevated ammonia
Renal impairment
Coagulopathy
Microvascular steatosis on liver biopsy

would suggest its use during pregnancy is
safe, although it is expensive and carries a
theoretical risk of fetal erythrocyte
destruction.21
In the setting of acute obstetric hemor-
rhage, treatment for ITP differs. Many
patients who will require acute treatment
will carry a prior diagnosis of ITP, but
present in labor with a lower-than-expected
platelet count. In a large retrospective series,
~30% of women with ITP were diagnosed
during pregnancy.19
The majority of these
will not have symptoms of thrombocytope-
nia; they may therefore go undiagnosed
until the time of delivery.
Patients with ITP should come to
attention at the time of labor by their
platelet count on routine complete blood
count at the time of admission, if not
diagnosed earlier. Approximately 15% of
individuals with ITP will have platelet
counts <50,000/μL at the time of delivery.
If significant thrombocytopenia is recog-
nized in advance of delivery, acute treat-
ment with intravenous immune globulin
1 g/kg/d for 2 to 3 days combined with
methylprednisolone 1 g/d for 3 days will
result in an acute increase in platelet
count typically within 24 to 48 hours.17
Often, when presented with a laboring
patient, there is insufficient time to induce
this increase in platelet counts. Intravenous
immune globulin with or without methyl-
prednisolone should still be considered in a
thrombocytopenic laboring patient, even
when it is unlikely that the treatment will
be effective by the time of delivery, as there
remains an increased risk of bleeding in the
immediate postpartum period. In the setting
of thrombocytopenia from ITP combined
with acute hemorrhage, platelet transfusion
may be necessary.22
Transfused platelets
have diminished survival in the patient with
ITP; therefore, platelet counts will not
respond as robustly as in a patient without
ITP.23
Overall, hemorrhagic complications
are uncommon in patients with ITP, and
are not always correlated with the degree of
thrombocytopenia.19
ITP is associated with neonatal throm-
bocytopenia in 12% to 28% of cases.18
There has been no correlation identified
between the severity of maternal throm-
bocytopenia and neonatal thrombocyto-
penia, nor do neonatal platelet levels
appear to be affected by maternal treat-
ment with corticosteroids or intravenous
immunoglobulin.12
The risk of neonatal
intracranial hemorrhage is low (< 1%),
and vaginal delivery remains the preferred
mode of delivery in patients with ITP
regardless of maternal platelet count,
although some suggest the avoidance of
vacuum assistance or use of high forceps
to reduce the risk of intracranial
hemorrhage in the neonate.18,24
Preeclampsia With Severe Features/
HELLP Syndrome
Thrombocytopenia from preeclampsia
with severe features and/or HELLP syn-
drome is more common than ITP. Most of
these patients will have significant hyper-
tension, although not all of those with
HELLP syndrome will be hypertensive.
Thrombocytopenia in HELLP syndrome
is typically observed in combination with
elevated liver transaminases and evidence
of hemolysis on peripheral smear or by
elevated lactate dehydrogenase.12
Maternal thrombocytopenia related to
preeclampsia with severe features or
HELLP syndrome typically resolves
spontaneously within 24 to 95 hours of
delivery.25
If acute blood loss is expected
in the setting of anticipated cesarean or
acute hemorrhage, platelet transfusion
can be used to reduce morbidity.
Other Causes of Thrombocytopenia
Additional causes of thrombocytopenia
in pregnancy include systemic lupus er-
ythematosus, thyroid disease, antiphos-
pholipid syndrome, lymphomas, and
infections such as human immunodefi-
ciency virus and hepatitis C. Drug-
induced thrombocytopenia is another
cause not directly related to pregnancy.
388 Bank et al

When recognized during the course of
pregnancy, treatment of the underlying
disorder is the primary means of increas-
ing the platelet count.26
The exceptions to this are hepatitis C,
where safety data surrounding treatment
during pregnancy is limited, and anti-
phospholipid syndrome, where treatment
for thrombocytopenia is similar to that
for ITP. Drug-induced thrombocytopenia
typically responds to cessation of the
offending agent within 1 to 10 days.
Medications that may be used in preg-
nancy and implicated in drug-induced
thrombocytopenia include acyclovir, pre-
dnisone, trimethoprim-sulfamethoxazole,
and cephalosporins.27
Platelet transfusion
should be used in the setting of acute
hemorrhage.
HUS and TTP
HUS and TTP are both characterized by
microangiopathic hemolytic anemia,
thrombocytopenia, neurological and re-
nal abnormalities, and fever. They are
rare disorders but can be life-threatening
if unrecognized and untreated. Only 30%
to 40% of individuals with these disorders
have the classic pentad of symptoms
described.28
Coombs-negative hemolytic
anemia and thrombocytopenia without
alternative cause are the only diagnostic
criteria required for the diagnosis of
TTP.29
HUS is primarily a disorder of child-
hood and adolescence. It is often pre-
ceded by abdominal pain and diarrhea.
HUS is rare during pregnancy and more
commonly presents within 48 hours to
10 weeks postpartum. It is characterized
by acute renal failure, resulting from
fibrin thrombi in the renal arterioles and
glomeruli.30
Aside from the severity of
renal failure, HUS and TTP have similar
laboratory findings, including marked
anemia and elevated lactate dehydro-
genase. Both are associated with a de-
crease in the enzyme ADAMTS13,
either through congenital deficiency or
acquired autoantibodies. ADAMTS13 is
a metalloproteinase responsible for
cleaving von Willebrand factor (vWF)
multimers. In its absence, these multi-
mers promote platelet aggregation, con-
tributing to the systemic microthrombi
characteristic of these disorders.29
ADAMTS13 activity is not always a
clinically useful assay; however, results
may not be available for several days.
Instead, it is most useful as a confirma-
tory assay and for the evaluation of
complications in subsequent pregnan-
cies, as a severe deficiency is associated
with an increased risk of relapse.29
Although hemorrhagic complications
are unusual in these disorders, it is
important to recognize HUS and TTP
as causes of thrombocytopenia, as a
delay in treatment results in increased
mortality. They are often difficult to
distinguish from the more common syn-
dromes of preeclampsia with severe fea-
tures and HELLP in pregnancy.31,32
In
many cases, patients with HUS or TTP
do not have hypertension characteristic
of preeclampsia or elevation of liver
transaminases as typically seen in
HELLP syndrome, but this is not always
true. The degree of hemolysis in HUS
and TTP is typically greater than ob-
served in HELLP syndrome, with higher
levels of lactate dehydrogenase and 2%
to 5% schistocytes on peripheral smear
compared with <1% with HELLP
syndrome.12
Laboratory abnormalities
do not typically improve with delivery
in TTP or HUS. The treatment of choice
for TTP is plasmapheresis. Plasmaphe-
resis may not be as effective in HUS;
supportive care and dialysis if needed
are the mainstays of treatment for this
disorder. Anticomplement therapy with
a C5 blocker is sometimes used in con-
sultation with hematology.33
Platelet
transfusion should be avoided as it
may precipitate or exacerbate the dis-
ease process and increase in-hospital
mortality.34

Acute Fatty Liver of Pregnancy (AFLP)
With an incidence of 1 per 5000 to 15,000
pregnancies, AFLP is a rare disorder that
typically presents with nausea, malaise,
dyspnea, and mental status changes.12
It
can also be accompanied by a low-grade
fever, hypertension, headache, or ascites.
Liver transaminases are elevated, and
hypoglycemia is common, along with
metabolic acidosis. Coagulopathy is also
present, manifested by a prolonged PT,
decreased fibrinogen, and thrombocyto-
penia. Hemoconcentration and an ele-
vated white blood cell count may also be
seen. While liver biopsy is the gold stand-
ard for diagnosis, this is rarely performed.
In research settings, the Swansea criteria
have been proposed as a tool to diagnose
AFLP (Table 1).35
The Swansea criteria
may also be used to predict those patients
at risk of developing significant maternal
complications from AFLP, including
acute liver failure, coma, acute kidney
injury, pulmonary edema, gastrointesti-
nal bleeding, and hepatic encephalop-
athy, along with fetal complications,
such as intrauterine fetal demise, neonatal
death, intrauterine distress, and neonatal
asphyxia.36
Treatment for AFLP is maternal stabi-
lization and delivery. Supportive care,
focusing on the correction of coagulop-
athy and electrolyte abnormalities, is
essential. As supportive care has im-
proved, the maternal mortality rate asso-
ciated with acute fatty liver has decreased
significantly; historically AFLP was asso-
ciated with a 70% maternal mortality
rate, but contemporary studies suggest
that the mortality rate is significantly
lower, <10%. Recovery is expected to
begin within 2 to 3 days of delivery.
However, some patients experience fur-
ther elevation of liver enzymes and wor-
sening coagulopathy over the first week
postpartum. Pancreatitis and fulminant
liver failure are rare but highly morbid
complications that may develop and
should be evaluated with serial laboratory
monitoring.30
Recent data suggests a 74%
transplant-free survival rate for preg-
nancy-associated liver failure. Overall,
40% to 50% of women who are listed for
transplant in the setting of AFLP are
ultimately delisted for improvement in
liver function, occurring over an average
of 3 days.37
Inherited Platelet Disorders
Inherited platelet disorders are an uncom-
mon cause of excessive bleeding. They can
be difficult to diagnose and there is little
evidence to base optimal management
upon, with most recommendations drawn
from small case series. For the purposes of
this discussion, the inherited platelet dis-
orders have been divided into categories
of mild and severe dysfunction.
Most patients with these disorders are
poor candidates for neuraxial anesthesia
due to a risk of epidural hematoma. As
most of these disorders are inherited,
there is also a risk that the fetus may
suffer from the same bleeding diathesis.
Invasive procedures such as scalp electro-
des and scalp sampling, as well as oper-
ative delivery are best avoided in this
population. Prenatal diagnosis is avail-
able in many cases to detect a fetus likely
to be affected with a severe bleeding
disorder.
DISORDERS WITH MILD PLATELET
DYSFUNCTION
Patients with disorders causing mild pla-
telet dysfunction may be asymptomatic
before delivery. These disorders are often
only manifested when a significant hemo-
static challenge is presented, such as
surgery. In some cases, childbirth will be
the first hemostatic challenge these pa-
tients encounter, unmasking the under-
lying disorder.
These disorders are rare; most are
estimated to have a worldwide prevalence
of <1000 cases.38
In many cases, the
platelet dysfunction is part of a larger
syndrome with other, more easily
390 Bank et al

recognized features. These disorders can
be classified into several types: inherited
thrombocytopenia, disorders of receptors,
disorders of platelet granules, and disor-
ders of phospholipid exposure.
MYH-9 thrombocytopenias are autoso-
mal dominant disorders involving defective
megakaryopoiesis due to a mutation in the
MYH-9 gene. These include May-Hegglin
anomaly and Sebastian, Fechter, and
Epstein syndromes.39
Other clinical features
of the syndrome include sensorineural hear-
ing loss, glomerulonephritis, and cataracts.
On peripheral smear, these patients have a
population of very large platelets.39
Hermansky-Pudlak syndrome is an au-
tosomal recessive disorder resulting in
defective platelet dense granules and ocu-
locutaneous albinism.40
Idiopathic dense-
granule disorder or δ-storage pool disease
is also in this category of platelet disorders
but has no other associated character-
istics. Specialized aggregation studies are
required for the diagnosis of both, and
reduced numbers or absence of dense
granules can be confirmed by electron
microscopy.40
Gray platelet syndrome is a disorder
reported to have both autosomal domi-
nant and recessive patterns of inheritance.
It is a deficiency of platelet α-granules,
and results in a characteristic appearance
of large, misshapen, agranular “gray”
platelets on peripheral smear.41
Treatment of inherited platelet disor-
ders is not required unless the platelet
count is <50,000/μL. Platelet transfusion
is generally recommended for counts low-
er than 30,000/μL.38
Tranexamic acid
may be used in cases where the platelet
count is between 30,000 and 50,000/μL.
Other mild platelet disorders will also
respond to tranexamic acid, and desmo-
pressin (DDAVP) may be helpful in con-
trolling acute bleeding. Tranexamic acid
is a derivative of the amino acid lysine
that inhibits the conversion of plasmino-
gen to plasmin, thereby reducing fibrin
degradation and stabilizing clots.42
Case
reports have evaluated the use of tranexa-
mic acid used prophylactically for pa-
tients with platelet storage pool disease43
and Glanzmann thrombasthenia,44
dis-
cussed below; however, this data is
limited.
DISORDERS WITH SEVERE PLATELET
DYSFUNCTION
Most patients with severe platelet dys-
function have symptoms present since
childhood. As infants, they may have
had significant bruising or bleeding with
vaccinations and teething. Epistaxis is
common, as is heavy menstrual bleeding
and obstetric hemorrhage. Invasive pro-
cedures are often a challenge, as excessive
bleeding is almost universal.38
Bleeding
requiring a blood transfusion after deliv-
ery has been noted in up to 50% of women
with Bernard-Soulier syndrome and
Glanzmann thrombasthenia.45
Bernard-Soulier Syndrome
Bernard-Soulier syndrome is usually an
autosomal recessive disorder with a prev-
alence of 1:1,000,000. An autosomal
dominant form also exists. It is charac-
terized by thrombocytopenia and large
platelets on peripheral smear. The under-
lying defect is absence or decreased ex-
pression of the glycoprotein Ib/IX/V
complex on the platelet surface, resulting
in deficient binding of vWF and therefore
deficient platelet adhesion.46
With regard to laboratory diagnosis,
bleeding time is almost always prolonged.
An alternative to measure bleeding time is
measuring closure time on the platelet
function analyzer-100, used in many
commercial laboratories. Closure times
for patients with Bernard-Soulier syn-
drome are more than 300 seconds.47
Thrombocytopenia is variable, however
large platelets are typically observed on
peripheral smear. Aggregation studies
show an absent ristocetin response, and
flow cytometry can confirm the deficiency
of glycoprotein Ib/IX/V.48
Treatment in

the setting of labor and delivery may
include antifibrinolytic therapy with tra-
nexamic acid or rFVIIa.42
The rFVIIa is
typically given as an intravenous bolus at
a dose of 90 μg/kg immediately before
delivery.38,49
The rFVIIa can be repeated
every 2 hours until it is clear that hemo-
stasis is effective. Platelet transfusion is
effective but controversial as these pa-
tients are at risk for development of
platelet alloantibodies due to multiple
transfusions. Human leukocyte antigen
and platelet antigen matched platelets
should be used whenever possible.
Glanzmann Thrombasthenia
An autosomal recessive disorder, Glanz-
mann thrombasthenia is characterized by
a deficiency or functional defect in plate-
let surface glycoprotein GPIIb/IIIa.50
GPIIb/IIIa mediates platelet binding to
adhesive proteins, fibrinogen, vWF, and
fibronectin; its absence or reduced func-
tionality results in defective platelet
aggregation.
Patients with Glanzmann thrombas-
thenia have normal platelet counts and
morphology, but bleeding times are
prolonged.51
Closure time on platelet
function analyzer-100 analysis exceed 300
seconds.52
Aggregation studies are abnor-
mal, and the diagnosis can be confirmed
with flow cytometry. Treatment options
are the same as those for patients with
Bernard-Soulier Syndrome: both tranexa-
mic acid and rFVIIa are effective.53,54
Platelet transfusion is a common intra-
partum treatment.55
Again, human leu-
kocyte antigen and platelet antigen
matched platelets are preferable to avoid
platelet alloimmunization.
OTHER DISORDERS OF
COAGULATION
Von Willebrand Disease (vWD)
vWD is the most common inherited bleed-
ing disorder, with a prevalence of 1.3%.56
It the result of either a quantitative
or qualitative deficiency in vWF. vWF
mediates platelet adhesion and serves as a
carrier for Factor VIII.
Three types of vWD have been de-
scribed. Type I is characterized by de-
creased levels of functionally normal
vWF and accounts for 70% to 80% of
vWD.57
Patients with type I vWD have
failed platelet aggregation in the presence
of ristocetin. Type II vWD results from
structurally abnormal vWF and accounts
for 20% of vWD patients. Patients with
type IIB also may have thrombocytope-
nia. Type III vWD is the result of com-
plete deficiency of vWF with resultant
secondary deficiency of factor VIII, and
accounts for 5% to 10% of cases.32
Many patients with vWD will not be
diagnosed until presented with a hemo-
static challenge such as delivery or sur-
gery. Bleeding during pregnancy is
uncommon after the first trimester be-
cause of a physiological increase in factor
VIII and vWF.58
This increase in vWF
usually does not benefit patients with type
II vWD, as the vWF remains structurally
and therefore functionally abnormal.
Furthermore, thrombocytopenia in pa-
tients with type IIB vWD may develop
or worsen during pregnancy due to plate-
let aggregation induced by abnormal
multimers. Patients with type III vWD
have no improvement in vWF or factor
VIII during pregnancy.58
Patients with vWD have a significantly
increased risk of postpartum hemorrhage,
with an incidence as high as 30% in
several case series.59
Both immediate
and delayed postpartum hemorrhage are
common. Immediate postpartum hemor-
rhage is seen more commonly in patients
with type II vWD and those with vWF
levels <50% of normal at term.60,61
This
risk can be significantly reduced with
appropriate prophylactic therapy. De-
layed postpartum hemorrhage (occurring
> 24 h after delivery) occurs frequently
because of a rapid decline in vWF and
factor VIII levels postpartum.
392 Bank et al

Diagnosis of vWD can be difficult. To
screen for all variants of vWD fully, the
following laboratory parameters should
be obtained: factor VII:coagulant activ-
ity, vWF:antigen (Ag), vWF:ristocetin
cofactor (Rco), ristocetin-induced platelet
aggregation, and vWF multimer
analysis.62
Type I vWD will have de-
creased vWF:Ag with a normal vWF:
Ag/vWF:Rco ratio. Type II variants are
characterized by decreased vWF:Ag/
vWF:Rco ratio, and abnormalities in
vWF multimers. Type III vWD will have
virtual absence of vWF.62
All of these
tests should be interpreted in concert with
hematologic consultation, as laboratory
abnormalities can be subtle.
Treatment for vWD includes DDAVP,
a synthetic analog of vasopressin that
increases plasma levels of vWF and factor
VIII transiently.57
It can increase circu-
lating levels of factor VIII and vWF to 3
to 5 times the basal levels within 30 mi-
nutes, with effects typically lasting 6 to
8 hours.63
It is most effective in patients
with type I vWD with structurally normal
vWF. It should be avoided in patients
with type IIB vWD as it may exacerbate
thrombocytopenia.
There are theoretical concerns about
the safety of DDAVP use in pregnancy:
its vasoconstrictive effect may reduce
placental blood flow or an oxytocic effect
may cause preterm labor. However, these
concerns have not been supported in
systematic reviews.64,65
There may be a
small risk of hyponatremia due to the
antidiuretic hormone effect of DDAVP,
particularly in combination with water
loading, as seen in 1 case report.66
Patients with factor VIII levels <50 IU/
dL should be treated with DDAVP before
delivery or anticipated bleeding event.
The usual dose is 0.3 μg/kg given intra-
venously. Intranasal DDAVP also is
available; a dose of 300 μg is standard
for adults. DDAVP should be given every
12 to 24 hours, using factor VIII levels to
guide the timing and balance the effect of
the medication, which typically lasts 8 to
10 hours, with the risk of tachyphylaxis,
or decreased response to recurrent
administrations.67
Alternatively, patients who do not
respond to DDAVP, including those with
type III vWD, should be treated with
vWF-factor VIII concentrates (such as
Humate-P or Alphanate SD/HT). The
goal of prophylaxis is to raise vWF and
factor III levels to 50 IU/dL. Levels
should be maintained for 3 to 5 days
postpartum given the risk of
bleeding.67,68
Tranexamic acid and cryo-
precipitate also may be used to control
acute hemorrhage. Some suggest that a
course of oral tranexamic acid may be
used for those affected by heavy lochia in
the weeks following delivery,68
however
the optimal dose, duration, and benefit of
treatment await further investigation.69
Hemophilia A (Factor VII Deficiency)
and Hemophilia B (Factor IX Deficiency)
Hemophilia A and B are X-linked disor-
ders resulting in congenital deficiency of
factor VIII and factor IX, respectively.70
Affected females are uncommon; how-
ever, carriers of these disorders may occa-
sionally have abnormal bleeding. Factor
VIII levels usually rise during pregnancy;
thus, carriers of hemophilia A usually do
not require prophylaxis or treatment for
hemorrhage at the time of delivery.71
Factor VIII level should be evaluated at
the initial prenatal visit and again in the
third trimester and at the time of delivery.
Levels <40 to 50 IU/dL at the time of
delivery or other invasive procedure, or
the setting of acute bleeding should
prompt treatment of hemophilia A car-
riers. DDAVP is an appropriate interven-
tion for these patients; rFVIII concentrate
is highly effective and is usually the treat-
ment of choice for acute bleeding.68
Hemophilia B carriers are more likely
to experience postpartum hemorrhage, as
levels of factor IX do not rise during the
course of pregnancy.71
These patients

should also have factor IX levels eval-
uated at the onset of pregnancy, in the
third trimester, and at the time of deliv-
ery. Hemophilia B carriers do not respond
to DDAVP and should receive prophy-
lactic factor IX concentrate for factor
levels <50 IU/dL before delivery.72
Factor VIII Inhibitors
Also known as acquired hemophilia A,
the development of antibodies against
factor VIII is a rare disorder with a
predilection for manifestation in the post-
partum period.73,74
It is typically diag-
nosed upon finding an isolated prolonged
PTT, which is not corrected by incubating
the patient’s plasma with equal volumes
of normal plasma (mixing study). The PT
should be normal, but factor VIII levels
will often be reduced. The diagnosis of an
inhibitor can be confirmed with the
Bethesda assay.
Treatment of patients with this disor-
der begins with increasing factor VIII
levels; therefore, DDAVP and/or factor
VIII concentrate can be used in cases of
mild bleeding. In the setting of acute
hemorrhage, rFVIIa and/or activated
prothrombin complex concentrates are
more effective.71
Immunosuppressive
therapy has been used successfully to
decrease inhibitor levels and induce re-
mission of this disorder. Spontaneous
remission is common but slow, occurring
in a median time of 30 months.75
Other Factor Deficiencies
Deficiencies of factors II, V, VII, X, XI,
and XIII are rare inherited disorders of
coagulation. Most will have a prolonged
PT and/or PTT at baseline. Prothrombin
(factor II) deficiency is rare but has been
associated with postpartum hemorrhage
in case reports. The treatment of choice
for patients with this disorder is pro-
thrombin complex concentrates, with the
goal of therapy to raise prothrombin
levels to 20 to 30 IU/dL.76
Factor V deficiency should be treated
with fresh-frozen plasma (FFP) at a dose
of 15 to 20 mL/kg based on general
surgical literature77
; there is limited expe-
rience with this disorder in pregnancy.
Inherited factor VII deficiency is the most
common of the inherited factor deficien-
cies. This disorder has a variable presen-
tation with regard to bleeding risk.78
The
treatment of choice for significant bleed-
ing is rFVIIa. Factor X deficiency also
has a variable presentation in terms of the
degree of abnormal bleeding. Factor X
levels increase during pregnancy, but
those with severe deficiency or a history
of significant bleeding may benefit from
treatment with FFP or prothrombin com-
plex concentrates.79
These agents would
also be the treatments of choice for acute
hemorrhage.
Factor XI deficiency, or hemophilia C,
is most commonly observed in the Ash-
kenazi Jewish population. The degree of
bleeding abnormality is variable in this
disorder and does not correlate well with
factor XI levels.80
Patients with levels
> 20 U/dL with no history of significant
bleeding do not require specific therapy at
the time of delivery, although the use of
tranexamic acid may be considered.
Those with levels <20 U/dL should re-
ceive prophylactic factor XI concentrate
during labor or before cesarean
delivery.81
Individuals with factor XIII deficiency
are at the highest risk for spontaneous
hemorrhage. This disorder has also been
associated with recurrent pregnancy loss.
Most patients require ongoing treatment
to attain a successful pregnancy. Unlike
the other factor deficiencies, the PT, PTT,
and bleeding time are normal. Diagnosis
is made with an abnormal clot solubility
test.82
Factor XIII levels typically fall
during pregnancy, and most patients will
require monthly infusions of factor XIII
concentrate to maintain a trough level
of > 3 U/dL.83,84
Treatment of acute
hemorrhage can be accomplished with
394 Bank et al

FFP or cryoprecipitate; however, factor
XIII concentrates are generally superior,
albeit less widely available. Use of tra-
nexamic acid for the treatment of acute
bleeding in pregnancy and postpartum in
the setting of severe factor XIII deficiency
has been reported.85
Disorders of Fibrinogen
Afibrinogenemia and hypofibrinogenemia
are rare inherited conditions with absent
or reduced levels of fibrinogen, respec-
tively. It is important to consider hepatic
disorders in patients suspected of an in-
herited fibrinogen disorder, as this is a
common cause of an acquired fibrinogen
deficit.86
Afibrinogenemia and hypofibrinogene-
mia may initially be detected during
an evaluation for heavy menstrual
bleeding.87
They are also associated with
recurrent pregnancy loss, both antepar-
tum and postpartum hemorrhage, and
well as impaired wound healing.88,89
In
hypofibrinogenemia, structurally normal
fibrinogen is present at levels <150 mg/
dL. Dysfibrinogenemia, in contrast, is a
functional disorder of fibrinogen. It is
often a dominantly inherited molecular
defect; however, it may also be
acquired.90
The most sensitive screening
test for this disorder is a prolonged
thrombin time. Patients with dysfibrino-
genemia are at significant risk for
thrombosis.91
They may only have sig-
nificant bleeding at the time of delivery,
or in the setting of combined hypofibri-
nogenemia and dysfibrinogenemia.92,93
Improved pregnancy outcomes for pa-
tients with hypofibrinogenemia/afibrino-
genemia have been reported with the use
of FFP or cryoprecipitate to maintain
levels of fibrinogen > 100 to 150 mg/dL
both antepartum and intrapartum.94
Pa-
tients with dysfibrinogenemia usually do
not require prophylaxis unless they also
have low levels of fibrinogen at the
time of delivery. Treatment of an acute
bleeding episode should be with FFP or
cryoprecipitate.90
Summary
Disorders of coagulation are relatively
uncommon as the sole cause of postpar-
tum hemorrhage. Historical clues may be
present, such as a family history of coag-
ulation disturbance, prior hemorrhage
with delivery, dental extraction, surgery,
or a history of heavy menstrual bleeding.
In some patients, the first sign of a
coagulation disorder will be obstetric
hemorrhage, as this may be their first
significant hemostatic challenge. Patients
in whom a disorder of coagulation is
known or suspected should have an ante-
partum evaluation, including hematology
consultation, to determine a plan for any
indicated antepartum therapy, and anes-
thesia to ensure the availability of the
appropriate medications and/or blood
products. Patients whose first manifesta-
tion of coagulation disturbance is obstet-
ric hemorrhage should receive standard
treatment for hemorrhage, with subse-
quent evaluation for disorders of coagu-
lation if indicated by personal or family
history, abnormal laboratory studies, or
clinical impression. Uterine contraction
remains as an important part of postpar-
tum hemostasis, even in patients with
abnormal coagulation; however, diagno-
sis of a coagulation disorder often
requires a high index of suspicion. Coa-
gulopathy should not be overlooked in
the evaluation of obstetric hemorrhage,
especially one persisting despite standard
treatment.
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398 Bank et al

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