BLEEDING DISORDERS IN

CHILDREN

Flerida Galsim-Hernandez, MD
Associate Professor II
UST Faculty of Medicine and Surgery
 OUTLINE

1. Review the normal control of bleeding

2. Discuss a practical approach to the
evaluation of a child with overt bleeding or
with a hx of ↑ bleeding
3. Discuss selection of the most appropriate
laboratory tests
4. Discuss some selected common causes of
inherited and acquired bleeding disorders
exposed endothelium --> ADP release for vasoconstriction, vWF for
platelet aggregation, pseudopods will form mesh --> platelet plug --> fibrin
formation
TF IX
Platelet
IXa
VII
TF Prothrombin
X
TF VIIa TF
Xa

v
W
F

VIII Thrombin
 v
W
F
Thrombin
VIII
TF
V
VIIIa

v TF VIIa XI
W
TF F IX XIa
IXa

VIIIa Va
Xa

X Prothrombin Thrombin
 Fibrinogen
TF

Thrombin
VIIIa

v Fibrin
W
TF F
(soluble)
XIII
VIIIa
XIIIa
TF

VIIIa

v Fibrin
W
TF F
(insoluble)

VIIIa
 OUTLINE

1. Review normal control of bleeding

2. Discuss a practical approach to the
evaluation of a child with overt bleeding or
with a hx of ↑ bleeding
3. Discuss selection of the most appropriate
laboratory tests
4. Discuss some selected common causes of
inherited and acquired bleeding disorders
 Practical Approach:
Evaluation of a child with bleeding

1. Comprehensive medical history, including

bleeding history
2. Family history
3. Detailed physical examination
4. Selected laboratory tests
 Medical History

1. Symptoms
a. mucocutaneous bleeding
epistaxis hematuria
gingival bleeding GI bleeding
menorrhagia
subcutaneous bleed

easy bruising-petechiae, ecchymosis

b. hemarthrosis hematoma muscle bleed
prolonged or delayed bleeding after
laceration/surgery
 Medical History

2. Severity
spontaneous or with trauma
correlation of symptoms with degree of injury
duration of bleeding

3. Age of onset
congenital vs acquired
mild bleeding disorders may not manifest
early in life
 Medical History

4. Response to hemostatic challenge

surgery: circumcision, tonsillectomy, tooth
extraction, etc
phlebotomy
immunization/intramuscular injection
suture placement/removal
childbirth Most common congenital bleeding
in woman-- von willebrand disease

*Absence of bleeding during surgery affecting the

mucosal surfaces usually rules out a cong bleeding
disorder.
 Medical History

5. Underlying medical conditions with

known associations with hemostatic
defects
liver disease
renal failure
connective tissue disorder
malabsorption syndrome
Vitamin K deficiency
myeloproliferative disorder
leukemia
 Medical History

6. Medications that can affect platelet function

Aspirin
NSAIDS - naproxen, ibuprofen, phenylbutazone,
piroxicam inhibits prostaglandin synthesis --> no
thromboxane --> no platelet aggregation

Ticlopidine
Antibiotics: PCN- carbenicillin, Pen G, ampicillin, ticarcillin,
nafcillin, azlocillin, mezlocillin
Cephalosporins – moxalactam, cefotaxime
Nitrofurantoin
Volume expanders: Dextran, hydroethyl starch
Heparin
Fibrinolytic agents
 Medical History

6. Medications that can affect platelet count

Quinidine
Penicillin
Anticonvulsants
Quinine
Sulfonamides
Digoxin
Heparin
 Medical History

6. Medications that affect clotting factors

anticoagulants: warfarin, heparin, LMW
heparin
antimetabolites: L-asparaginase
 Family history

Sites and patterns of bleeding of the child's

parents, siblings and any other affected
relatives

Symptoms, response to hemostatic challenge

 Family History

Hemophilia - sex-linked recessive

Type 1VWD - autosomal dominant

Type 2N VWD - autosomal recessive

 Physical Examination

Disorder of vessel wall & Disorder of Coagulation

platelet (number or fxn)

• recurrent or prolonged • delayed bleeding esp into

epistaxis muscles and joints
• menorrhagia, hematuria, • hematomas
GI bleed
• easy bruising – petechiae,
ecchymosis (cutaneous,
mucosal)
Physical Examination
Physical Examination
Physical Examination
 OUTLINE

1. Review the normal control of bleeding

2. Discuss a practical approach to the
evaluation of a child with overt bleeding or
with a hx of ↑ bleeding
3. Discuss selection of the most appropriate
laboratory tests
4. Discuss some selected common causes of
inherited and acquired bleeding disorders
 Assessment of the role of platelets
in hemostatic plug formation
1. Platelet count
2. Visualization of platelets in a blood smear
3. Skin bleeding time
4. Platelet aggregation tests
5. Platelet flow cytometry
6. Platelet electron microscopy
Note: PFA 100
 CBC Platelet Count

Automated blood counters more accurate than

manual platelet counting (coefficient of
variation 10-25%)

At low platelet counts (<20,000/mm3), manual

platelet count more accurate
Hanseler E et al. Estimation of the lower
limits of manual & automated platelet
counting. AmJ Clin Patho/1996; 105:782-7
Normal Platelets
 Large Platelets

– young platelets
- destructive cause of thrombocytopenia
Pale-appearing platelets

- lack normal α - granules

 Schistocytes

- may be the only clue to the etiology of

thrombocytopenia in TTP and HUS
- also found in DIC
Ivy Bleeding Time

by Template
(Simplate)

 more sensitive
than Duke

normal BT= 1-9 mins

Platelet Function Analyzer (PFA)

-time taken for platelet plug to

occlude a microscopic aperture
in a membrane coated with
platelet agonists
-more useful as a screening test
for bleeding disorders
-quantitative, simple, rapid, and
reproducible

Jilma B. Lab Clin Med

2001;138:152-63
 Skin Bleeding Time

Platelet count < 100,000/uL – associated with

prolonged bleeding time
normal bleeding time with low platelet = ITP, if 50,000-100,000
platelets

Disproportionate prolongation – may suggest

qualitative defect or vWD
Screening tests on the integrity of
soluble clotting factors
1. Activated partial thromboplastin time (aPTT)
intrinsic + common pathway

2. Prothrombin time or PT and international

normalized ratio (INR) extrinsic + common pathway

3. Thrombin time final pathway

4. Fibrinogen level DIC

 aPTT

Crossover PT
Scheme of
Coagulation

TT
 Evaluation of isolated prolonged APTT and
heparin effect eliminated
Prolonged APTT intrinsic pathway

1:1 Mixing with normal plasma

Corrects to Partial or
normal range no correction

Assays for Lupus anticoagulant or

FVIII, FIX, FXI, FXII Specific factor inhibitor

Diagnosis (or) Test for “slow activators”

 Specific tests

Platelet function studies

Fibrinogen assay
Clotting factor activity assays
vWAg assay
vWfactor assay (Ricof)
Urea clot lysis time
Inhibitor assays
DIC work-ups – Fibrinogen, FDP, D-dimer
 Fibrinogen

Present in highest concentration in plasma

Normal adult level: 175 to 400mg/dL
Significantly reduced
acquired (DIC, liver dysfunction, fibrinolytic
states)
hereditary coagulopathies (a- dys- and hypo -
fibrinogenemia)
 Hemostasis in newborn

All newborns have ‘abnormal’ coagulation

All have low levels of coagulation factors
Liver immaturity
Worse in prematurity: at significant bleeding
risk
Abnormal fibrinogen F 10, 9, 7, 2

Low levels of vitamin K dependent factors

by 48-72nd hr after birth
return to normal by 7-10th DOL
 Hemostasis in newborn

Fibrinogen, FV, FVIII, vWF, and platelets are

near-normal in the later stages of gestation
F8 F5
Natural anticoagulants – Protein S, Protein C,
F2 AT-III reduced

Prolonged APTT, PT, TT (up to 2x normal adult

range)

Different ref. ranges for NB and up to 6 months

 OUTLINE
1. Review platelet plug formation in normal
hemostasis
2. Discuss a practical approach to the
evaluation of a child with overt bleeding or
with a hx of ↑ bleeding
3. Discuss selection of the most appropriate
laboratory tests to arrive at a working dx
4. Discuss some selected common causes
of inherited and acquired bleeding
disorders in an ambulatory setting
 Easy Bruising

Small bruises (< size of a quarter) - frequently

seen on LE of active youngsters
Up to 30% of children report bruises as often as
weekly
Rare for children less than 1 y/o
(+) FHx for hemorrhagic tendencies or suspicion
of non-accidental trauma - indication for basic
screening
IMMUNE THROMBOCYTOPENIC PURPURA

Etiology
Viral infection 1-4 weeks before the onset of
symptoms in 50-65% of cases
Autoantibody directed against the platelet
surface
Ab-coated platelets are recognized by Fc
receptor on the splenic macrophages,
ingested and destroyed.
life threatening bleed if less than 20, 000 platelets = GI bleed, intracranial bleed

IMMUNE THROMBOCYTOPENIC PURPURA

Clinical features
Previously healthy 1-5 year old child
Generally well-looking, unless with serious
bleeding (CNS, intra-abdominal)
Normal PE except for mucocutaneous
bleeding
Splenomegaly rare inc platelet in 2 weeks, complete
recovery of platelet in 6 months
70-80% -spontaneous remissions w/in 6 mo
10-20% - develop chronic ITP platelet still low after
6 months
IMMUNE THROMBOCYTOPENIC PURPURA

Laboratory features
Severe thrombocytopenia, normal or ↑ platelet
size, Hgb and WBC are normal.
Hgb may be ↓ if there have been significant
blood loss
BMA:
normal granulocytic & erythrocytic series
characteristically normal or ↑ numbers of
megakaryocytes.
IMMUNE THROMBOCYTOPENIC PURPURA

Indications for bone marrow aspiration

1. Abnormal WBC count or differential count
2. Unexplained anemia
3. Findings suggestive of BM disease

In adolescents with new-onset ITP, ANA test

should be done to evaluate for SLE
IMMUNE THROMBOCYTOPENIC PURPURA

No medical treatment; educate

- 30-70% of children with severe

thrombocytopenia achieve platelet counts of
50k after 3 weeks w/o treatment

- appropriate for >20k with no bleed, more

strongly for >30k (ASH)
IMMUNE THROMBOCYTOPENIC PURPURA

Medical treatment may be instituted

American Society of Hematology

recommends treatment with IVIG or a
glucocorticoid:
- platelet counts less than 20,000/μL
plus significant mucosal membrane
bleeding
- those with platelet counts less than
10,000/μL and minor purpura
IMMUNE THROMBOCYTOPENIC PURPURA

Medical treatment may be instituted

British Pediatric Hematology Group

- a child's condition rather than the platelet
count steers management
- children with bruising but without mucosal
or more severe hemorrhage may be treated
by observation alone, irrespective of the
platelet count.
IMMUNE THROMBOCYTOPENIC PURPURA

Intravenous Immunoglobulin (IVIG)

MOA: appears to downregulate Fc-mediated
phagocytosis of antibody-coated platelets; does not
alter bone marrow findings
- induces a rapid rise in PC (usually>20× 109/L) in
95% of patients within 48 hr

Disadvantages:
effect lasts 4 weeks, expensive, time consuming

Side effects:
fever, chills,aseptic meningitis, anaphylaxis in IgA
deficiency
IMMUNE THROMBOCYTOPENIC PURPURA

Intravenous Anti-D
MOA: RBC-Ab complexes bind to macrophage Fc
receptors & interfere with platelet destruction

-induces a rise in platelet count to>20× 109/L in 80–

90% of patients within 48–72 hr

-induces mild hemolytic anemia

- effective to Rh (+) individuals only; response

more likely if spleen is present
IMMUNE THROMBOCYTOPENIC PURPURA

Steroid
MOA: improves capillary resistance thereby
improving platelet economy
inhibits platelet Ab production
inhibits phagocytosis of Ab-coated platelets in
the spleen

- given for 2–3 wk or until PC to>20× 109/L with a

rapid taper

- significant side effects with prolonged use

ASH data bank
IMMUNE THROMBOCYTOPENIC PURPURA

Platelet transfusion
- not recommended except in the presence of life
threatening bleed
Splenectomy
1. Older child (> 4 yr) with severe ITP >1 yr & whose
symptoms not controlled with tx
2. When life-threatening hemorrhage (ICH)
complicates acute ITP, if PC not corrected rapidly
with transfusion of platelets, admin of IVIG & steroids

- lifelong risk of overwhelming postsplenectomy inf

- vaccination and Penicillin prophylaxis
Who among the following patients with ITP
would require medical treatment:

A. A 3-year old boy with a platelet count of

20,000/mm3
B. A 4-year old female with profuse
gumbleeding
C. A 3-year old girl with small ecchymosis on
the shin with a platelet count of
50,000/mm3
D. A 4-year old boy with a platelet count of
10,000/mm2
B and D
 HEMOPHILIA A OR B
Most serious congenital coag factor deficiency
X-linked recessive
↓ blood levels of procoagulant FVIII or FIX;
inadequate thrombin generation leads to
failure to form a tightly cross-linked fibrin clot
to support the platelet plug
1: 5,000-6,000 live male births, no apparent
racial predilection
F8 F9

Hemophilia A = 85%; Hemophilia B = 10-15%

High rate of spontaneous mutation (≈30%)
 HEMOPHILIA A OR B

Severity based on patient’s circulating FVIII/FIX

Severe <1%
Moderate 1-5%
Mild 6 to < 50%

Lower limit of FVIII & FIX in normal indiv ≈ 50%

Hemostatic level for FVIII >30-40%
FIX >25-30%
 HEMOPHILIA A OR B

Clinical features
hemarthroses – hallmark of hemophilia
easy bruising
intramuscular hematomas
bleeding from minor traumatic lacerations
life threatening bleeding from vital structures
(CNS, upper airways) or by exsanguinations
(external, GI, or iliopsoas hemorrhage)
 HEMOPHILIA A OR B

Laboratory tests:
aPTT - always prolonged (2-3x) in severe
hemophilia
- slightly prolonged or may be normal in
mild/moderate hemophilia
Mixing study – with correction
FVIII/FIX levels – below the normal range
Measure vWf levels in mild-mod hemophilia
 HEMOPHILIA A OR B

Treatment
1. Factor replacement therapy – mainstay of tx
- degree of correction depends on the site &
nature of bleeding episode
Factor VIII or IX concentrates
Cryoprecipitate – rich in factor VIII, vWF,
fibrinogen and FXIII
cryosupernate - with FIX
FFP – contains all clotting factors
 HEMOPHILIA A OR B

Treatment
2. Ancillary Tx
DDAVP (Stimate)- ↑ FVIII levels 2.5 – 6 fold
by releasing endogenously produced FVIII in
mild hemophiliac
Antifibrinolytic agent – prevents activation of
plasminogen to plasmin
Ex. epsilon aminocaproic acid
tranexamic acid
 HEMOPHILIA A OR B

Treatment
3. Supportive care
Anticipatory guidance, psychosocial
intervention, avoid anti-platelet drugs,
immunization, periodic screening for TTI
Complications:
Chronic arthropathy
Development of factor inhibitor
Risk of transfusion-transmitted infection
Psychosocial and economic burden
A 2-year old boy with severe Hemophilia A
refused to walk for 3 days now. On PE, he
has right ankle joint swelling. How much
FVIII concentrate would you infuse this 12 kg
child? 20 IU/kg q12 hrs

A. 120 IU every 12 hours

B. 240 IU every 12 hours
C. 120 IU once a day
D. 240 IU once a day

B
 common in females presenting with menorrhagia

VON WILLEBRAND DISEASE

Most common bleeding disorder with quali-

tative &/or quantitative defects of multimeric
glycoprotein, VWF
biochem evidence in 1-2% of population
biochem evidence + bleeding Hx - 0.1% pop
Autosomal inheritance
Von Willebrand has 2 functions:
1. plays an integral role in mediating adherence of
platelets
2. binds & transports FVIII
 Classification of vWd

Type Freq Comment

autosomal dominant
1 ~80% Partial quantitative deficiency of VWF
2 15-20% Qualitative defects of VWF
2A Variants w/ ↓platelet-dependent fxn assoc w/
selective absence of HMW VWF multimers
2B Variants w/ ↑affinity for binding platelet GP1b
leading to a reduction of HMW VWF multimer
2M Variants w/ ↓platelet-dependent fxn assoc w/
a normal distribution of VWF multimers
autosomal recessive
2N Variants w/ markedly ↓ affinity for FVIII
3 Rare Virtually complete absence of VWF
Differences between von Willebrand Disease and Hemophilia A

von Willebrand Dis Hemophilia A

Symptoms Bruising Joint bleeding
Mucosal bleeding like Muscle bleeding
epistaxis, menorrhagia
Sexual dist Males=Females Males
Frequency 1:200 to 1:500 1:6000 males
AbN protein vWF Factor VIII
Inhibitor freq Rare 14-25% of patients
Bleeding time Often abnormal Usually normal
PTT Normal or ↑ Prolonged
Factor VIII Borderline or ↓ ↓ or absent
vWF Ag ↓ or absent Normal or ↑
vWF R:Co Dec. or abnormal Normal or increased
vWF multimers Normal or abnormal Normal
 VON WILLEBRAND DISEASE

Accurate diagnosis requires the following

measurements:

1. VWF: Ag
2. VWF:RCo
3. F VIII:C
4. VWF multimer analysis
5. Platelet count
 VON WILLEBRAND DISEASE

Treatment
Type I – DDAVP
Type II – vWF replacement therapy
Platelet type (Pseudo) vWD = platelet
transfusion
Type III - vWF replacement therapy
DDAVP maybe effective in the following
situations:

A. Type I vWD
B. Type III vWD
C. Hemophilia A, mild
D. Hemophilia B, mild

A and C
 Henoch-Schonlein purpura

Also known as anaphylactoid purpura

Common vasculitis of small vessels with
cutaneous and systemic complications
Most common cause of nonthrombocytopenic
purpura in children
Etiology: unknown
 Henoch-Schonlein purpura

Clinical features
1. Palpable cutaneous purpura

dependent areas of the body or in areas of

greater tissue distensibility
2. Arthritis – in 2/3 of patients; localized to the
knees and ankles concomitant with edema
3. Visceral involvement
GIT – colicky abd pain; > ½ occult heme (+)
stools
Kidneys – 25-30% with nephritis or nephrosis
 Henoch-Schonlein purpura

Laboratory evaluation
1. To determine normal hemostatic function by
screening tests: PC, PBS, BT, PT and aPTT
2. To determine existence and degree of visceral
involvement, particularly GI and renal disease.
Tests: Hgb/Hct, retic count, guiac testing of the
stool, WBC and diff.’l count, urinalysis, serum
creatinine or BUN
 Henoch-Schonlein purpura

Definitive Dx of vasculitis: biopsy of cutaneous

site showing leukocytoclastic angiitis – when
presentation is atypical

Treatment
Symptomatic
Steroids for intestinal complications
Hydrostatic reduction or resection of
intussusceptions when necessary
 Henoch-Schonlein purpura

Complications
Nephrotic syndrome
bowel perforation
Testicular torsion

Prognosis
Self-limited with excellent prognosis
<1% persistent renal disease
 Vitamin K Deficiency
Hemorrhagic Disease of the Newborn

- accentuation and prolongation of

deficiency of factors II, VII, IX, and X
between the 2nd and 7th DOL

- characterized by bleeding that tends to be

GI, nasal, subgaleal, intracranial, or post-
circumcision

-
Hemorrhagic Disease of the Newborn
Early-onset HDN
Onset: birth to 24 hrs
Risk factor: mother treated with drugs that interfere
with Vit K function: Ex. phenobarbital, phenytoin
Classic HDN
Onset: 2-7 days old
Bleeding: GIT, ENT-mucosal, ICH
Risk factors: Vit K def, breastfeeding
Late-onset HDN
Onset: > 2 weeks
Risk factor: often assoc with Vit K malabsorption
Ex. neonatal hepatitis, biliary atresia
 Vitamin K Deficiency
Lab: ↑ PT, ↑PTT in severe cases

Treatment:
- IM administration of 1 mg of vit K at birth
prevents the ↓ in vit K–dependent factors in
full-term infants, but it is not uniformly
effective in the prophylaxis of HDN
- may be effectively treated with a slow IV
infusion of 1-5 mg of vit K1, FFP or whole
blood for serious bleeding
 Vitamin K Deficiency
Post-neonatal Vitamin K deficiency
Secondary to:
lack of oral intake of vitamin K
alterations in the gut flora due to long-term
use of broad-spectrum antibiotics
liver disease
malabsorption of vitamin K
Disseminated intravascular coagulation

Widespread intravascular deposition of fibrin

with consumption of coagulation factors
and platelets leading to:
tissue ischemia and necrosis
generalized hemorrhagic state
microangiopathic hemolytic anemia.
Consequence of inappropriate and
excessive activation of the hemostatic
system by an underlying disorder
 Disseminated intravascular coagulation
Trigger factor(s)

Activation of Platelet
coagulation Vessel wall
damage activation
cascade

Fibrin-platelet End organ

thrombosis damage
Lysis and repair
Coagulation Low platelet count Fibrinolysis
factor deficiency activation

FDPs
Generalised generated
bleeding tendency
Main causes of DIC in clinical practice

Infection Shock
Septicemia (Gram -ve) Extensive surgical trauma
Burns
Viremia Heat stroke
Protozoa (malaria) Liver disease
Malignancy Cirrhosis
Metastatic carcinoma Acute hepatic necrosis
AML (especially M3) Transplantation
Obstetric disorders Acute rejection
Septic abortion Extracorporeal circulation
Abruption Intravascular haemolysis
Eclampsia ABO incompatibility
Amniotic fluid embolus Snake bite
Placenta previa
Disseminated intravascular coagulation

Clinical features
bleeding
anemia caused by hemolysis
tissue necrosis of many organs most
spectacularly seen as infarction of large
areas of the skin, subcutaneous tissues
or kidneys
Disseminated intravascular coagulation

Laboratory features

Low platelet count

Evidence of microvascular hemolysis
Prolonged PT, APTT, TT
Low fibrinogen
Raised FDP and D-dimer
Disseminated intravascular coagulation

Treatment
1. Treat the trigger
2. Restore normal homeostasis by correcting
shock, acidosis & hypoxia
3. Blood components tx for patients with
bleeding
platelet conc, cryoprecipitate, FFP, PRBC
Laboratory features of the common bleeding dso
PC BT PT PTT

HSP NL NL / h NL NL

ITP i h NL NL

Hemophilia NL NL NL h
tx: factor replacement therapy

vWD NL/i  NL NL/h

tx: DDAVP

HDN NL NL h NL - early
tx: vit K h- late

DIC
tx underlying cause of DIC
i h h h

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