Bleeding Disorders in Congenital Syndromes - American ...
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Bleeding Disorders in
Congenital Syndromes
Susmita N. Sarangi, MD, Suchitra S. Acharya, MD
Pediatricians provide a medical home for children with congenital abstract
syndromes who often need complex multidisciplinary care. There are
some syndromes associated with thrombocytopenia, inherited platelet
disorders, factor deficiencies, connective tissue disorders, and vascular
abnormalities, which pose a real risk of bleeding in affected children
associated with trauma or surgeries. The risk of bleeding is not often an
obvious feature of the syndrome and not well documented in the literature.
This makes it especially hard for pediatricians who may care for a handful
of children with these rare congenital syndromes in their lifetime. This
review provides an overview of the etiology of bleeding in the different
congenital syndromes along with a concise review of the hematologic
and nonhematologic clinical manifestations. It also highlights the need
and timing of diagnostic evaluation to uncover the bleeding risk in these
syndromes emphasizing a primary care approach.
Bleeding Disorders and Thrombosis Program, Cohen
Children with congenital syndromes these patients as part of surveillance Children’s Medical Center of New York, New Hyde Park,
New York
with multiple anomalies need a or before scheduled procedures
multidisciplinary approach to and recommends guidelines for Drs Sarangi and Acharya contributed to the
their care, along with continued appropriate and timely referral to the conceptualization, content, and composition of the
surveillance for rare manifestations hematologist. manuscript and approved the final manuscript as
submitted.
such as a bleeding diathesis, which
may not be evident at diagnosis. This Achieving hemostasis is a complex DOI: 10.1542/peds.2015-4360
accompanying bleeding diathesis process starting with endothelial Accepted for publication Aug 15, 2016
due to thrombocytopenia or other injury that results in platelet plug Address correspondence to Suchitra S. Acharya,
coagulation defects may be a part of formation, which is then strengthened MD, Bleeding Disorders and Thrombosis Program,
the syndrome that is not routinely by deposition of fibrin formed Cohen Children’s Medical Center of New York, 269-
01 76th Ave, Suite 255, New Hyde Park, NY 11040.
addressed. Consequently, this may go by the proteolytic coagulation
E-mail: sacharya@northwell.edu
unrecognized in these children until cascade. Platelets initially attach
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
they face hemostatic challenges, which to subendothelial collagen and
1098-4275).
is not uncommon (given the number von Willebrand factor (vWF) via
Copyright © 2017 by the American Academy of
of corrective surgeries performed glycoproteins VI and 1bα (GPVI,
Pediatrics
for the congenital defects) in this GPIbα). This leads to activation of
FINANCIAL DISCLOSURE: The authors have
population leading to unanticipated platelets releasing Thromboxane
indicated they have no financial relationships
surgical bleeding. Counseling for these A2 (TxA2) and conforming the relevant to this article to disclose.
families should include discussions glycoprotein IIb/IIIa (GPIIb/IIIa)
FUNDING: No external funding.
regarding potential spontaneous or receptor on the platelet surface into
POTENTIAL CONFLICT OF INTEREST: The authors
trauma-related bleeding associated its high affinity state, which now
have indicated they have no potential conflicts of
with these syndromes that can binds to fibrinogen and vWF. This interest to disclose.
evolve over time. This review aims further leads to release of platelet
to highlight congenital syndromes granule contents (fibrinogen, Factor
where hemostatic defects have been V, platelet factor 4, Calcium, ADP, To cite: Sarangi SN and Acharya SS. Bleeding
Disorders in Congenital Syndromes. Pediatrics.
reported, aid the treating primary care ATP, serotonin, vWF) leading to an
2017;139(2):e20154360
physician (PCP) to adequately workup extremely procoagulant surface and
Downloaded from www.aappublications.org/news by guest on January 21, 2021
PEDIATRICS Volume 139, number 2, February 2017:e20154360 STATE-OF-THE-ART REVIEW ARTICLEplatelet aggregation. The stage is of which 17% (43 samples) were made soon after birth. Although
now set for the cascade of serine due to chromosomal anomalies. The survival beyond infancy is rare, life
proteases (factors V, VII, VIII, IX, X, prevalence was 54% in Trisomy expectancy is improving. Recognizing
XI, XII, XIII) activated by the release 13, 86% in Trisomy 18, 31% in thrombocytopenia is important
of tissue factor, which culminate in Turner syndrome, and 6% in because these conditions have
the cleaving of thrombin to form Trisomy 21–Down syndrome (DS). associated cardiac, respiratory, and
an insoluble fibrin mesh leading However, Hord et al7 reported mild craniofacial anomalies that may need
to a stable clot at the site of injury. to moderate thrombocytopenia corrective or palliative surgeries.
With the many players involved in (platelet counts 40 000–100 000/ Surgical planning in these patients
coagulation, it can be seen how the μL) in 28% of neonates with DS. The needs a multidisciplinary team with
clinical bleeding phenotype can be exact mechanism is not known, but screening blood work to identify
modified by gene–gene interactions is thought to be due to decreased thrombocytopenia, which if present
by improving or worsening the platelet production, from chronic will need platelet transfusions pre-
integrity of clot formation directly fetal hypoxia, which also leads to and postoperatively depending upon
or indirectly. Therefore, this review intrauterine growth retardation.8 the complexity of the surgery guided
will focus on congenital syndromes by the hematologist.
DS (Trisomy 21) is also associated
associated with quantitative Turner syndrome (45, X) can
with other hematologic findings,
(thrombocytopenia) and qualitative be associated with transient
such as polycythemia, neutropenia,
platelet function defects (ie, defects thrombocytopenia (31% of patients6)
abnormal circulating blasts,
in platelet generation or defects at 1 in the newborn period. Due to the
erythroblastosis, and giant platelets.9
or more levels of platelet activation) single functional X chromosome, girls
Approximately 10% of neonates with
and coagulation factor deficiencies. can inherit X-linked conditions like
DS have transient myeloproliferative
It will also highlight congenital hemophilia, but this has only very
disorder, which can present with
syndromes where bleeding can rarely been described.12 Therefore,
isolated thrombocytopenia or
result from defects in the underlying prolonged bleeding events warrants
thrombocytosis, leukocytosis, or
connective tissue or anatomic referral to a hematologist for workup.
persistent peripheral blood blasts.
malformations that increase Gastro-enteral bleeding can occur in
These abnormal blood cells will self-
predisposition to bleeding. It will Turner syndrome due to associated
resolve in most infants by 3 months
further discuss basic evaluation of inflammatory bowel disease or
after birth; however, 20% can have
these patients on the basis of a high often unrecognized intestinal
more progressive disease. Both
index of suspicion and highlight what telangiectasias (incidence of 7%).13
transient myeloproliferative disorder
phenotypes need specialist referral
and myeloid leukemia associated DiGeorge syndrome (22q11.2 del)
for both health maintenance and
with DS (ML-DS), which presents is the most common micro deletion
prevention of surgical bleeding and
at 1 to 4 years of age, have somatic syndrome with associated mild
discuss general treatment principles.
mutations in the megakaryocyte macrothrombocytopenia in 30%
Table 1 and Supplemental Tables 5
erythroid transcription factor of patients resulting from deletion
and 6 summarize the key features of
GATA-1.10,11 ML-DS has a preceding of the contiguous GP1BB gene in
the congenital syndromes discussed
myelodysplastic phase with patients the deleted Chromosome 22q11
in this review.
presenting with progressive locus, which codes for the subunit
anemia and thrombocytopenia, of the platelet adhesion receptor.1
which then develops into leukemia. Immune dysfunction is common in
COMMON CONGENITAL SYNDROMES
ASSOCIATED WITH A BLEEDING DS-associated acute lymphoblastic these patients and it is estimated
DIATHESIS leukemia develops after age 4 years, that immune thrombocytopenic
presenting with cytopenias, and often purpura is 200 times more common in
Chromosomal Syndromes lower platelet counts than ML-DS these patients as compared with the
patients. Therefore, all DS patients general population.14,15 These platelet
A fault in chromosome distribution
should have a complete blood cell abnormalities need to be identified
during cell division leads to
count at birth and if found to have early on and specifically before
aneuploidy, which can be associated
any hematologic abnormalities corrective cardiac surgeries. Close
with thrombocytopenia but is rarely
should be referred to hematology. collaboration with a hematologist
severe. Hohlfeld et al6 in a study of
5194 fetal blood samples (17 to 41 Other trisomies such as Trisomy 13 before these surgeries will help avert
weeks) reported 4.7% samples (247 and Trisomy 18 have very distinct bleeding complications.
samples) with thrombocytopenia clinical patterns (Table 1), Noonan syndrome is a relatively
(platelet countsTABLE 1 Features of Congenital Syndromes Associated With Thrombocytopenia
Disorder Incidence Clinical Features Incidence of Thrombocytopenia When to Refer to Hematology
Trisomy 21 1 in 660 Cognitive impairment, hearing 7–28%a All patients with any hematologic
issues, thyroid issues, heart abnormalities
defects, gastroenteral atresias,
cataracts
Trisomy 13 1 in 5000 Cleft lip and palate, polydactyly, 54%a (All patients had platelet counts Platelet count 100 000/μL)
omphalocele, VSD, PDA, neural
tube defects
Trisomy 18 1 in 5000 Dolichocephaly, micrognathia, 86%a (20% with platelet counts 50 000– Platelet count(EDS) being the most prevalent.
Although collagen proteins are
an integral part of capillary
scaffolding, they also contribute
to platelet activation, adhesion,
and aggregation. EDS is a clinically
and genetically heterogeneous
group of conditions with varying
degrees of skin hyperextensibility,
joint hypermobility, delayed
wound healing, and atrophic skin
scarring. There are 5 subtypes with
a combined prevalence rate of 1
in 5000 individuals. Type IV EDS
(vascular type) carries the gravest
prognosis affecting medium and large
sized vessels. It can initially present
as easy bruising and gum bleeding,
but depending on the vessels affected
can have bleeding from every
possible site of the body, including
fatal intraabdominal bleeding.23 The
other subtypes of EDS manifest with
soft, fragile hyperextensible skin
along with joint dislocations and
bony abnormalities.23 The diagnosis
is often challenging in children,
especially when there is no family
history and can lead to extensive
hemostasis-related bleeding
workups, which are often normal.
In the office setting, clinicians can
use the Beighton scoring system
(Fig 1) for evaluation of joint
hypermobility and refer patients
FIGURE 1
with high scores to the geneticist The Beighton Scoring system for joint hypermobility. Degree of mobility assessed by passive
for further evaluation and maneuvers in 5 joints. Total score: 0–9. Hypermobility score: ≥5. (Figure reproduced with permission
confirmatory genetic testing.24,25 from Arthritis Research UK; http://www.arthritisresearchuk.org)
Capillary fragility is common among
all subtypes with variable degrees Abnormalities in Vasculature (telangiectasias) without intervening
of platelet function defects and capillaries, which have a higher
coagulation factor deficiencies Hereditary hemorrhagic propensity to bleed due to inherently
(factors VIII, IX, XI, XII, and XIII) telangiectasia (HHT) or Osler– elevated perfusion pressures. In HHT,
being reported.23 Desmopressin Weber–Rendu syndrome is a telangiectasias can develop in the
has been shown to reduce bleeding common autosomal inherited nasal mucosa within the first decade
risk and postoperative bleeding disorder with altered defects in and worsen with age, presenting with
in pediatric patients with EDS, vascular integrity with an incidence severe and recurrent nosebleeds.
suggesting that a weakened platelet of 1 in 5000 individuals. The While evaluating significant and
collagen interaction underlies underlying genes ENG, ACVRL1, prolonged epistaxis in a pediatric
the bleeding tendency in EDS.26 SMAD4 encode proteins leading patient, the PCP should inquire
Therefore, individuals with suspected to elevated expression of vascular about bleeding from other sites,
or confirmed diagnosis of EDS with endothelial growth factor.27 This presence of anemia and gastro-
any bleeding symptoms or planned leads to characteristic clinical enteral bleeding, and strokes related
surgical procedures should be manifestations of dilated and to arterio venous malformations
referred to a hematologist. tortuous postcapillary venules among close family members. It
Downloaded from www.aappublications.org/news by guest on January 21, 2021
4 SARANGI and ACHARYAmight be difficult to make a diagnosis TABLE 2 The Curacao Diagnostic Criteria for proteins of the coagulation
in childhood as characteristic HHT cascade), specimen handling,
telangiectasias are often not present Criteria Definition and interpretation and should be
until later or present as benign- Epistaxis Spontaneous, recurrent carried out in conjunction with an
looking mucocutaneous red spots nosebleeds experienced hematologist who can
that go unnoticed by providers. Telangiectasias Multiple, at characteristic accurately interpret the clinical and
The Curacao Criteria (Table 2) is a sites (lips, oral cavity, laboratory findings. Although light
fingers, nose)
validated scoring system developed transmission aggregometry and
Visceral Pulmonary, liver, cerebral,
to help elucidate a diagnosis of HHT involvement spinal, or gastrointestinal its modification lumiaggregometry
as nosebleeds and telangiectasias are vascular malformations are used for initial screening for
common in the general population.28,29 Family history A first-degree relative with platelet function defects, there are
Otorhinolaryngologists should be definite HHT limitations of standardization and
Diagnostic criteria
consulted early on in a child with reproducibility. However, it can
Definite HHT 3 or 4 criteria are present
prolonged recurrent nose bleeds to Probable HHT 2 criteria are present help identify platelet adhesion or
look for these telangiectasias without HHT unlikely Only 1 criterion is present aggregation defects, platelet granule
which the diagnosis may be missed release defects on the basis of which
until a later encounter with a life- further confirmatory testing can be
threatening bleeding episode. with known inherited platelet carried out.
disorders.32 Wiskott–Aldrich syndrome is a
RARE CONGENITAL SYNDROMES rare autosomal recessive disorder
Supplemental Table 5 outlines
ASSOCIATED WITH A BLEEDING due to defects in the WASP gene
the various features of inherited
DIATHESIS (Xp 11.22) with an incidence of 4
thrombocytopenic syndromes. The
per million live births.3 The clinical
underlying molecular defect can be
Inherited Platelet Disorders features classically include the
restricted to platelets alone, or in
triad of microthrombocytopenia
Many of the inherited some cases can involve other cells
(platelet counts 5000–50 000/
thrombocytopenias are clinically thereby resulting in multisystem
μL) presenting as bruising and
mild and may go unrecognized dysfunction. Evaluation of the
purpura in the neonatal period,
unless faced with hemostatic patient and the family for presence
eczema that develops around
stressors such as menses, surgery, of immunodeficiency, hearing loss,
infancy and immune defects with
trauma, or childbirth.30 A thorough albinism, and renal findings will point
recurrent sinopulmonary infections
bleeding history is a crucial to an underlying syndromic cause of
in midchildhood. A high index of
component in the evaluation of thrombocytopenia. This is further
suspicion should prompt referral to
these patients, including obtaining complicated by the fact that all
a hematologist who may recommend
previous blood counts if available. components of the syndrome may not
splenectomy to ameliorate
Particularly, time should be devoted be present in affected individuals and
bleeding symptoms associated with
to eliciting the family history with therefore a high index of suspicion is
thrombocytopenia or bone marrow
special attention to hemostatic key to their diagnoses. While working
transplantation, which is usually
stressors, such as menorrhagia, up these patients, it is important
curative (Table 1 and Supplemental
bleeding after teeth extractions, to collect fresh blood samples
Table 6).
blood transfusions after surgery, or with citrate as the anticoagulant
unexplained anemia. Platelet counts to eliminate the phenomenon
Bone Marrow Failure Syndromes
should be determined in family of pseudothrombocytopenia.
members with bleeding symptoms. Automated platelet counters are not Thrombocytopenia in inherited
The pattern of bruising and bleeding accurate in the presence of macro bone marrow failure syndromes
disproportionate to trauma should or micro thrombocytopenia and (IBMFS) presents as a component of
raise suspicion for nonaccidental manual inspection of peripheral progressive marrow failure, which
trauma even in patients in whom smears under Giemsa or Wright is the hallmark of these syndromes.
congenital platelet disorders are stain provide important information Thrombocytopenia may present in
suspected.31 The use of standardized regarding platelet number, size, and the neonatal period in congenital
bleeding assessment tools is very granularity. After recognition of amegakaryocytic thrombocytopenia
useful in this setting. The Pediatric these syndromes, further diagnostic and thrombocytopenia with
Bleeding Questionnaire identified evaluation of platelet disorders needs absent radii (TAR) manifesting
high bleeding scores (>96% of careful preparation (a nontraumatic as petechial bleeding and rarely
patients) in a cohort of 23 patients blood draw to preserve component leading to catastrophic intracranial
Downloaded from www.aappublications.org/news by guest on January 21, 2021
PEDIATRICS Volume 139, number 2, February 2017 5hemorrhage. Unlike other IBMFS, syndrome and a number of other should be based on the gestational
the thrombocytopenia in TAR platelet abnormalities described, age, onset of thrombocytopenia (72 hours
suggesting that nonlife-threatening recognize that abnormal platelet indicating postnatally acquired
procedures could be delayed until function usually persists despite infections), and the clinical status
after infancy. Fanconi anemia resolution of thrombocytopenia in of the newborn (sick versus well
presents with thrombocytopenia as some patients. Therefore, formal appearing). Karyotype testing should
the first hematologic manifestation platelet function testing with a plan be done in all obviously dysmorphic
during midchildhood, whereas in for platelet transfusions are indicated infants with thrombocytopenia.
Shwachman–Diamond syndrome it before major procedures despite Inherited causes of thrombocytopenia
appears later, having been preceded normal platelet counts.5 are in general rare and rarely
by neutropenia for variable amounts present in the newborn period. If a
of time.33 Supplemental Table 6 Other Congenital Disorders clear family history is present, the
outlines the various IBMFS that hematologist should be consulted
have thrombocytopenia as part of Storage disorders such as Gaucher to guide appropriate timing of
the syndrome. The pathognomonic disease and Niemann–Pick disease confirmatory testing and help
physical features can aid in present with splenomegaly either manage thrombocytopenia in
recognizing the underlying IBMFS, due to direct splenic infiltration or the neonatal period. This should
but it is important to realize that portal hypertension. While caring include a comprehensive delivery
half of these patients may not be for these patients, it is important plan with contraindication for
recognized until adulthood.34 to keep in mind that platelets can instrumental delivery, vacuum,
pool and sequester inside the or use of fetal scalp monitoring.
Chromosomal Disorders abnormally enlarged spleen, which Early onset thrombocytopenia
can lead to acute life-threatening 50 000/ μL are good
rare inherited disorder that can
platelet function defects.39 Once clues pointing to an underlying
have transient thrombocytopenia
these disorders are diagnosed, it inherited defect. In the setting of a
at birth.35 More recently a higher
would be important to obtain a well appearing infant with isolated
incidence of chronic immune
baseline platelet count and refer to a thrombocytopenia and absence of
thrombocytopenia (ITP) in these
hematologist for bleeding symptoms any other features, it is reasonable
patients has also been described
or before a surgical procedure to treat for immune-mediated causes
(see Table 1).4 Self-injurious
for a comprehensive evaluation of thrombocytopenia (neonatal
behavior is often a component of
of the bleeding phenotype and alloimmune thrombocytopenia)
the syndrome that compounded
recommendations for surgery. until platelet antigen incompatibility
with thrombocytopenia can lead
can be demonstrated between
to an increased risk of intracranial
mother and infant serologically.
bleeding. It has been proposed to GENERAL GUIDELINES FOR HEALTH Most allo or auto antibodies against
get platelet counts for these patients MAINTENANCE AND MANAGEMENT OF neonatal platelets clear from the
at diagnosis, with any unusual BLEEDING SYMPTOMS circulation over time with platelet
bleeding symptoms and at 5 yearly
counts normalizing within 1 to 2
intervals if asymptomatic and refer Newborn Period
weeks in most infants. Persistence
to hematology for severe bleeding
Thrombocytopenia is encountered of thrombocytopenia beyond 8 to 12
symptoms.4
fairly commonly (up to 25% weeks42 after birth should warrant a
Jacobsen syndrome (11q of admitted newborns) in the hematology consult especially in the
syndrome) is perhaps the most well NICUs with rates increasing with absence of any immunologic factors
described congenital syndrome prematurity.40 The challenge lies or genetic syndromes.
with thrombocytopenia that in identifying which of these can
poses significant morbidity to stem from an underlying inherited Infancy and Beyond
affected children. The clinical disorder. Fetal platelets are found in The reader is referred to health
phenotype is variable with circulation by ∼5 weeks of gestation supervision guidelines for various
macrothrombocytopenia a frequent and start reaching adult values by genetic syndromes, which are a
(88.5% of patients) feature of the 22 weeks.41 The diagnostic approach useful resource for physicians
Downloaded from www.aappublications.org/news by guest on January 21, 2021
6 SARANGI and ACHARYATABLE 3 Management of Common Bleeding Symptoms With Identified Platelet/Coagulation Defects
Symptom General and Preventive Associated With Platelet Associated With Coagulation Interventions Useful for Severe Symptoms
Measures Defect Factor Deficiency
Epistaxis Place patient in sitting Local application of Local application of Bleeding lasting >10 min despite hemostatic
position with neck forward. hydrophilic powder such hydrophilic powder such measures, >5 episodes per year: refer
Firmly compress tip of nose as NasalCeasea as NasalCeasea to ENT for electrocauterization, nasal
for 20 min. packing for persistent or profuse
bleeding.
Daily saline nasal lubrication Aminocaproic acid 50–100 Aminocaproic acid 100 mg/ HHT patients may need laser ablation or
and humidification of room mg/kg/dose every 6 h kg/dose every 6 h × 7 d embolization
air. ×7d
Do not: Stick toilet paper, Desmopressinb intranasal rVIIa (used in Glanzmann thrombasthenia
cotton balls in nose as can spray 150 μg/dose: 2 refractory to platelet transfusions)—
dislodge clot sprays for adult, and 1 referral to hematology dose: 90 μg/kg
Do not: squeeze bony part of spray forwith other indicated systemic
hemostatic therapy because of
abundance of fibrinolysis in the
mouth. Children with a high risk of
bleeding should avoid contact sports,
heavy exercise, or isometric exercise
and wear protective pads to avoid
deep hematomas and bruising.26
Nonweight bearing exercises such as
aqua therapy should be encouraged
to promote a healthy lifestyle. Some
of these children can have restrictive
diets and vitamin K and vitamin C
may need to be supplemented, the
deficiencies of which can aggravate
the underlying bleeding disorder.
Common bleeding symptoms and
their management are addressed in
Table 3.
Antifibrinolytic agents (ε amino
caproic acid and tranexamic acid)
inhibit plasmin activity, thereby
strengthening clot formation and
can be used for prevention of minor FIGURE 2
trauma-induced or minor surgical Suggested approach to sequential presurgical evaluation for children with congenital syndromes
bleeding especially involving mucosal with known or suspected bleeding diathesis. The laboratory workup should start with an initial
surfaces that are rich in fibrinolytic screen and a more exhaustive workup can be done in conjunction with the hematologist on the
basis of known hemostatic defects for the specific congenital syndrome and the bleeding phenotype
enzymes in areas such as the mouth, of the individual patient. aBleeding phenotype: prolonged (>10 min), persistent (>5 episodes/year)
nose, uterus, and gastrointestinal nose bleeds, petechiae with minor trauma, bleeding while brushing teeth, heavy menstrual bleeding,
tract. Desmopressin (1-deamino- prolonged bleeding after tooth eruption or extractions; prolonged bleeding after a procedure
requiring a red cell transfusion, >1 cm bruises especially palpable in nature after minor trauma.
8-D arginine vasopressin) increases bHigh risk procedures: craniosynostosis surgery, multiple teeth extraction especially wisdom teeth,
platelet aggregation by increasing plastic or vascular procedures, cardiac procedures, scoliosis surgery, neurosurgery, liver or kidney
plasma levels of vWF and factor VIII, biopsy. cLow risk procedures: simple dental extraction, bronchoscopy, central venous catheter
thus improving platelet adhesion removal, cutaneous biopsy, GI endoscopy with biopsy, laparoscopic abdominal surgery. dInclude
factor XI levels in patients with Noonan syndrome.
and function. It has been shown
to be useful in various platelet
secretion and granule defects, EDS and therefore should be reserved studies are needed to evaluate
and Noonan syndromes, where it for serious bleeding symptoms. the impact of thromboelastogram
can improve platelet function and In some cases, judicious and to improve patient outcomes in
promote hemostasis.26,47–49 Both tailored use of fresh-frozen plasma bleeding disorders.
1-deamino-8-D arginine vasopressin (FFP), cryoprecipitate, and rVIIa
and/or antifibrinolytic agents may be indicated. The use of
can be used as monotherapy or rVIIa is approved in Glanzmann’s GUIDELINES FOR MANAGEMENT
adjuvant therapies to more definitive thrombasthenia where it improves BEFORE SURGICAL PROCEDURES
treatment. Hemostasis therapy platelet aggregation and fibrin and Patients suspected to have a
should be tailored on the basis of thrombin generation.50 Point of care congenital syndrome with a
the underlying hemostatic defect, devices, such as thromboelastogram, bleeding diathesis (symptomatic
severity of bleeding symptoms, or which can quantify global hemostasis or asymptomatic) must have a
hemostatic challenge of planned and monitor response to therapeutic sequential evaluation at least 2 to 4
surgery and results of the bleeding agents, are increasingly being weeks before a scheduled surgical
evaluation. Although platelet explored in clinical settings such as procedure as proposed in Fig 2.
transfusion seems straightforward, trauma and surgery,51 which can Bleeding assessment tools are useful
the development of alloantibodies provide improved bleed management to get a standardized bleeding
may cause platelet refractoriness and patient outcomes. Further history and calculate bleeding scores,
Downloaded from www.aappublications.org/news by guest on January 21, 2021
8 SARANGI and ACHARYATABLE 4 The Components and Scoring of the Pediatric Bleeding Questionnaire
Symptom/Score –1 0 1 2 3 4
Epistaxis — No or trivial (≤5 per year) >5 per year or >10 min Consultation only Packing, cauterization, or Blood transfusion, replacement
duration antifibrinolytics therapy, or desmopressin
Cutaneous — No or trivial (≤5 per year) >1 cm and on trauma Consultation only — —
Minor wounds — No or trivial (≤5 per year) >5 per year or >5 min Consultation only or steri- Surgical hemostasis or Blood transfusion, replacement
duration strips antifibrinolytics therapy, or desmopressin
Oral cavity — No Reported at least once Consultation only Surgical hemostasis or Blood transfusion, replacement
antifibrinolytics therapy, or desmopressin
Gastrointestinal tract — No Identified cause Consultation or Surgical hemostasis, —
spontaneous antifibrinolytics, blood
transfusion, replacement
therapy or desmopressin
Tooth extraction No bleeding in at least None done or no bleeding Reported, no consultation Consultation only Resuturing, repacking, or Blood transfusion, replacement
PEDIATRICS Volume 139, number 2, February 2017
2 extractions in 1 extraction antifibrinolytics therapy, or desmopressin
Surgery No bleeding in at least None done or no bleeding Reported, no consultation Consultation only Surgical hemostasis or Blood transfusion, replacement
2 surgeries in 1 antifibrinolytics therapy, or desmopressin
Menorrhagia — No Reported or consultation Antifibrinolytics or D&C or iron therapy Blood transfusion, replacement
only contraceptive pill use therapy, desmopressin, or
hysterectomy
Postpartum No bleeding in at least No deliveries or no Reported or consultation D&C, iron therapy or Blood transfusion, —
2 deliveries bleeding in 1 delivery only antifibrinolytics replacement therapy, or
desmopressin
Muscle hematoma — Never Posttrauma, no therapy Spontaneous, no therapy Spontaneous or traumatic, Spontaneous or traumatic requiring
requiring replacement surgical intervention or blood
therapy or desmopressin transfusion
Hemarthrosis — Never Posttrauma, no therapy Spontaneous, no therapy Spontaneous or traumatic, Spontaneous or traumatic requiring
requiring replacement surgical intervention or blood
therapy or desmopressin transfusion
Central nervous system — Never — — Subdural, any intervention Intracerebral, any intervention
Othera — No Reported Consultation only Surgical hemostasis, Blood transfusion, replacement
antifibrinolytics or iron therapy, or desmopressin
therapy
Reprinted with permission from Bowman M, Riddel J, Rand ML, Tosetto A, Silva M, James PD. Evaluation of the diagnostic utility for von Willebrand disease of a pediatric bleeding questionnaire. J Thromb Haemost. 2009;7(8): Table S1. —, score not
available for this particular system.
a Includes postcircumcision, umbilical stump, cephalhematoma, macroscopic hematuria, postvenipuncture, and conjunctival hemorrhage.
Downloaded from www.aappublications.org/news by guest on January 21, 2021
9which can help recognize individual contraindicated depending on the 4. Lambert MP, Jackson LG, Clark D,
bleeding risk. The components of the level of thrombocytopenia and other Kaur M, Krantz ID, Deardorff MA.
Pediatric Bleeding Questionnaire are hemostatic defects. The incidence of thrombocytopenia
presented in Table 4 for review.52 in children with Cornelia de Lange
syndrome. Am J Med Genet A.
A thorough head to toe physical
CONCLUSIONS 2011;155A(1):33–37
examination to identify and uncover
bleeding risk should focus on Abnormalities in hemostasis 5. Mattina T, Perrotta CS, Grossfeld P.
hyperextensibility, telangiectasias, leading to clinical bleeding are an Jacobsen syndrome. Orphanet J Rare
palpable bruises, splenomegaly, often unidentified component of Dis. 2009;4:9
ecchymoses, and petechiae. All many congenital syndromes. These 6. Hohlfeld P, Forestier F, Kaplan C, Tissot
medications and alternative therapies abnormalities are important for the JD, Daffos F. Fetal thrombocytopenia:
(including herbal preparations) PCP to recognize and anticipate, a retrospective survey of 5,194
should be carefully reviewed, and thereby prompting timely referral fetal blood samplings. Blood.
to the hematologist to adequately 1994;84(6):1851–1856
any medications known to affect
hemostasis should be discontinued or manage these patients to prevent 7. Hord JD, Gay JC, Whitlock JA.
substituted. A basic workup should catastrophic bleeding. Thrombocytopenia in neonates with
include a complete blood count, trisomy 21. Arch Pediatr Adolesc Med.
PT, and aPTT with mixing studies 1995;149(7):824–825
(when PT/aPTT are prolonged), ABBREVIATIONS 8. Watts TL, Roberts IAG. Haematological
which helps distinguish a clotting aPTT: activated partial thrombo- abnormalities in the growth-restricted
factor deficiency from nonspecific plastin time infant. Semin Neonatol. 1999;4:41–54
coagulation inhibitors. In syndromes DS: Down syndrome 9. Webb D, Roberts I, Vyas P. Haematology
with known qualitative platelet EDS: Ehlers-Danlos syndrome of Down syndrome. Arch Dis Child
defects, platelet function analysis FFP: fresh-frozen plasma Fetal Neonatal Ed. 2007;92(6):
(PFA-100), which has replaced the HHT: hereditary hemorrhagic F503–F507
bleeding time, should be included as telangiectasia 10. Lange BJ, Kobrinsky N, Barnard
part of the initial workup if available. IBMFS: inherited bone marrow DR, et al. Distinctive demography,
Further testing should be guided by failure syndromes biology, and outcome of acute myeloid
a pediatric hematologist who can ITP: immune thrombocytopenia leukemia and myelodysplastic
then order confirmatory testing. ML-DS: myeloid leukemia associ- syndrome in children with Down
Knowledge of the underlying platelet ated with Down syndrome: Children’s Cancer Group
Studies 2861 and 2891. Blood.
abnormality can guide further syndrome
1998;91(2):608–615
platelet function testing because the PCP: primary care physician
use of specific platelet agonists can PT: prothrombin time 11. Rainis L, Bercovich D, Strehl S, et al.
limit the amount of blood drawn in TAR: thrombocytopenia with Mutations in exon 2 of GATA1 are early
events in megakaryocytic malignancies
pediatric patients. A multidisciplinary absent radii
associated with trisomy 21. Blood.
team involving the surgeon, vWF: von Willebrand factor
2003;102(3):981–986
hematologist, and anesthesiologist
should tailor a treatment plan before 12. Panarello C, Acquila M, Caprino
surgery for these patients with the D, Gimelli G, Pecorara M, Mori PG.
REFERENCES
Concomitant Turner syndrome
judicious use of platelets and other
1. Budarf ML, Konkle BA, Ludlow LB, and hemophilia A in a female with
blood components to avoid allo- an idic(X)(p11) heterozygous at
et al. Identification of a patient with
immunization especially because Bernard-Soulier syndrome and a locus DXS52. Cytogenet Cell Genet.
patients with clinical syndromes deletion in the DiGeorge/velo-cardio- 1992;59(4):241–242
may require more than 1 corrective facial chromosomal region in 22q11.2. 13. Eroglu Y, Emerick KM, Chou PM,
procedure. The risk of bleeding due Hum Mol Genet. 1995;4(4):763–766 Reynolds M. Gastrointestinal bleeding
to any underlying thrombocytopenia 2. Briggs BJ, Dickerman JD. Bleeding in Turner’s syndrome: a case report
in part depends upon the nature disorders in Noonan syndrome. Pediatr and literature review. J Pediatr
of the surgery, critical need Blood Cancer. 2012;58(2):167–172 Gastroenterol Nutr. 2002;35(1):84–87
for maintaining postoperative
3. Bolton-Maggs PHB, Chalmers EA, 14. Akar NA, Adekile AD. Chromosome
hemostasis and promoting healing, Collins PW, et al; UKHCDO. A review 22q11.2 deletion presenting with
and individualized target platelet of inherited platelet disorders with immune-mediated cytopenias,
count depending upon the type guidelines for their management on macrothrombocytopenia and platelet
of surgery. Regional anesthesia behalf of the UKHCDO. Br J Haematol. dysfunction. Med Princ Pract.
and epidural catheters may be 2006;135(5):603–633 2007;16(4):318–320
Downloaded from www.aappublications.org/news by guest on January 21, 2021
10 SARANGI and ACHARYA15. Liang HP, Morel-Kopp MC, Curtin 27. Shovlin CL. Hereditary haemorrhagic congenital dysmegakaryopoietic
J, et al. Heterozygous loss of telangiectasia: pathophysiology, thrombocytopenia (Paris-Trousseau)
platelet glycoprotein (GP) Ib-V-IX diagnosis and treatment. Blood Rev. associated with giant platelet alpha-
variably affects platelet function 2010;24(6):203–219 granules and chromosome 11 deletion
in velocardiofacial syndrome 28. Shovlin CL, Guttmacher AE, Buscarini E, at 11q23. Blood. 1995;85(7):1805–1814
(VCFS) patients. Thromb Haemost. et al. Diagnostic criteria for hereditary 38. White JG. Platelet storage pool
2007;98(6):1298–1308 hemorrhagic telangiectasia (Rendu- deficiency in Jacobsen syndrome.
16. Strullu M, Caye A, Lachenaud J, et al. Osler-Weber syndrome). Am J Med Platelets. 2007;18(7):522–527
Juvenile myelomonocytic leukaemia Genet. 2000;91(1):66–67
39. Czapek EE, Deykin D, Salzman EW.
and Noonan syndrome. J Med Genet.
29. Van Gent MWF, Post MC, Mager JJ, Platelet dysfunction in glycogen
2014;51(10):689–697
et al. Diagnostic Curacao Criteria for storage disease type I. Blood.
17. de Haan M, vd Kamp JJ, Briët E, HHT; are they still valid? Hematology 1973;41(2):235–247
Dubbeldam J. Noonan syndrome: Meeting Rep. 2009;3(4):13
40. Roberts I, Stanworth S, Murray NA.
partial factor XI deficiency. Am J Med
30. Drachman JG. Inherited Thrombocytopenia in the neonate.
Genet. 1988;29(2):277–282
thrombocytopenia: when a low platelet Blood Rev. 2008;22(4):173–186
18. Sharland M, Burch M, McKenna count does not mean ITP. Blood.
41. Sola-Visner M. Platelets in the neonatal
WM, Paton MA. A clinical study of 2004;103(2):390–398
period: developmental differences
Noonan syndrome. Arch Dis Child.
31. Carpenter SL, Abshire TC, Anderst JD; in platelet production, function,
1992;67(2):178–183
Section on Hematology/Oncology and and hemostasis and the potential
19. Massarano AA, Wood A, Tait RC, Committee on Child Abuse and Neglect impact of therapies. Hematology
Stevens R, Super M. Noonan syndrome: of the American Academy of Pediatrics. (Am Soc Hematol Educ Program).
coagulation and clinical aspects. Acta Evaluating for suspected child abuse: 2012;2012:506–511
Paediatr. 1996;85(10):1181–1185 conditions that predispose to bleeding.
42. Chakravorty S, Roberts I. How I
20. Sharland M, Patton MA, Talbot S, Pediatrics. 2013;131(4). Available at:
manage neonatal thrombocytopenia.
Chitolie A, Bevan DH. Coagulation-factor www.pediatrics.org/cgi/content/full/
Br J Haematol. 2012;156(2):155–162
deficiencies and abnormal bleeding 131/4/e1357
in Noonan’s syndrome. Lancet. 43. Bull MJ; Committee on Genetics.
32. Biss TT, Blanchette VS, Clark DS,
1992;339(8784):19–21 Health supervision for children
Wakefield CD, James PD, Rand ML.
with Down syndrome. Pediatrics.
21. Bertola DR, Carneiro JDA, D’Amico EA, Use of a quantitative pediatric
2011;128(2):393–406
et al. Hematological findings in Noonan bleeding questionnaire to assess
syndrome. Rev Hosp Clin Fac Med Sao mucocutaneous bleeding symptoms 44. Frías JL, Davenport ML; Committee on
Paulo. 2003;58(1):5–8 in children with a platelet function Genetics and Section on Endocrinology.
disorder. J Thromb Haemost. Health supervision for children
22. Sharland M, Patton M, Chittolie A, with Turner syndrome. Pediatrics.
2010;8(6):1416–1419
et al. Coagulation factor abnormalities 2003;111(3):692–702
in Noonan syndrome. J Med Genet. 33. Alter BP. Inherited bone marrow failure
1990;27:646 syndromes. In: Nathan DG, Orkin SH, 45. Romano AA, Allanson JE, Dahlgren
Ginsburg D, Loot AT, eds. Nathan and J, et al. Noonan syndrome:
23. De Paepe A, Malfait F. Bleeding and
Oski’s Hematology of Infancy and clinical features, diagnosis, and
bruising in patients with Ehlers-
Childhood. Vol. 1. 6th ed. Philadelphia, management guidelines. Pediatrics.
Danlos syndrome and other collagen
PA: WB Saunders; 2003:281–365 2010;126(4):746–759
vascular disorders. Br J Haematol.
2004;127(5):491–500 34. Alter BP. Diagnosis, genetics, 46. Bassett AS, McDonald-McGinn DM,
and management of inherited Devriendt K, et al; International 22q11.2
24. O’Brien SH. An update on pediatric
bone marrow failure syndromes. Deletion Syndrome Consortium. Practical
bleeding disorders: bleeding scores,
Hematology (Am Soc Hematol Educ guidelines for managing patients with
benign joint hypermobility, and platelet
Program). 2007;1:29–39 22q11.2 deletion syndrome. J Pediatr.
function testing in the evaluation of the
2011;159(2):332–9.e1
child with bleeding symptoms. Am J 35. Fryns JP, Vinken L. Thrombocytopenia
Hematol. 2012;87(suppl 1):S40–S44 in the Brachmann-de Lange syndrome. 47. Stine KC, Becton DL. DDAVP therapy
Am J Med Genet. 1994;49(3):360 controls bleeding in Ehlers-Danlos
25. Beighton P, Solomon L, Soskolne
syndrome. J Pediatr Hematol Oncol.
CL. Articular mobility in an African 36. Gangarossa S, Schiliró G,
1997;19(2):156–158
population. Ann Rheum Dis. Mattina T, Scardilli S, Mollica F,
1973;32(5):413–418 Cavallari V. Dysmegakaryopoietic 48. Grange CS, Heid R, Lucas SB, Ross
thrombocytopenia in patients with PL, Douglas MJ. Anaesthesia in a
26. Shovlin CL, Nunes ME, Ruymann
distal chromosome 11q deletion. parturient with Noonan’s syndrome.
FB, et al. Hereditary haemorrhagic
Blood. 1996;87(11):4915–4916 Can J Anaesth. 1998;45(4):332–336
telangiectasia: pathophysiology,
diagnosis and treatment. Blood Rev. 37. Breton-Gorius J, Favier R, 49. Nurden AT, Freson K, Seligsohn
2010;24(6):203–219 Guichard J, et al. A new U. Inherited platelet disorders.
Downloaded from www.aappublications.org/news by guest on January 21, 2021
PEDIATRICS Volume 139, number 2, February 2017 11Haemophilia. 2012;18(4 suppl review of the literature. Haemophilia. 52. Bowman M, Riddel J, Rand ML, Tosetto
4):154–160 2014;20(4):464–471 A, Silva M, James PD. Evaluation of the
50. Rajpurkar M, Chitlur M, Recht M, 51. Jeger V, Zimmermann H, Exadaktylos diagnostic utility for von Willebrand
Cooper DL. Use of recombinant AK. The role of thrombelastography disease of a pediatric bleeding
activated factor VII in patients with in multiple trauma. Emerg Med Int. questionnaire. J Thromb Haemost.
Glanzmann’s thrombasthenia: a 2011;2011:895674 2009;7(8):1418–1421
Downloaded from www.aappublications.org/news by guest on January 21, 2021
12 SARANGI and ACHARYABleeding Disorders in Congenital Syndromes
Susmita N. Sarangi and Suchitra S. Acharya
Pediatrics originally published online January 6, 2017;
Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/early/2017/01/04/peds.2
015-4360
References This article cites 52 articles, 15 of which you can access for free at:
http://pediatrics.aappublications.org/content/early/2017/01/04/peds.2
015-4360#BIBL
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
Administration/Practice Management
http://www.aappublications.org/cgi/collection/administration:practice
_management_sub
Practice-Based Learning & Development
http://www.aappublications.org/cgi/collection/practice-based_learnin
g_-_development_sub
Hematology/Oncology
http://www.aappublications.org/cgi/collection/hematology:oncology_
sub
Blood Disorders
http://www.aappublications.org/cgi/collection/blood_disorders_sub
Permissions & Licensing Information about reproducing this article in parts (figures, tables) or
in its entirety can be found online at:
http://www.aappublications.org/site/misc/Permissions.xhtml
Reprints Information about ordering reprints can be found online:
http://www.aappublications.org/site/misc/reprints.xhtml
Downloaded from www.aappublications.org/news by guest on January 21, 2021Bleeding Disorders in Congenital Syndromes
Susmita N. Sarangi and Suchitra S. Acharya
Pediatrics originally published online January 6, 2017;
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/early/2017/01/04/peds.2015-4360
Data Supplement at:
http://pediatrics.aappublications.org/content/suppl/2017/01/04/peds.2015-4360.DCSupplemental
Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since 1948. Pediatrics is owned, published, and trademarked by
the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2017
by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.
Downloaded from www.aappublications.org/news by guest on January 21, 2021You can also read
