Bleeding tendency

Prof. Mohamed Moostafa

LEARNING OBJECTIVES
1- To Know and understand the physiology of normal hemostasis
2- To Enumerate the causes of bleeding disorders in children
3- To have a systematized approach for diagnosing child with bleeding
4- To Identify common bleeding disorders based on clinical and
laboratory characteristics and know lines of managements

NORMAL HEMOSTASIS
PHASES OF HEMOSTASIS:
- vasoconstriction
- Endothelial injury and formation of the platelet plug; through:
A) Platelet adhesion is by binding of platelet surface receptor
GPIb to von Willebrand factor (VWF) in the subendothelium
B) Platelet aggregation through binding GPIIb/IIIa receptor on
the platelet surface to fibrinogen
This mechanism is tested in vitro by platelet count, platelet
function tests and VWF assay

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 N.B. Bleeding time is historically used for a long time as a
diagnostic tool, but it is subjective, lacking sensitivity and
specificity

- Formation of fibrin clot by the coagulation cascade:

a) The intrinsic pathway involves activation of factor IXa which

in presence of VIIIa activates factor X. Tested in vitro by
activated partial thromboplastin clotting time [aPTT]).

b) The extrinsic pathway involves activation of VII (factor VIIa)

which in presence of tissue factor activates factor X. tested in
vitro by in vitro by prothrombin time [PT]).

c) Common pathway: Both pathways converge on the activation

of factor X which that converts prothrombin to thrombin.
Thrombin converts fibrinogen from a soluble plasma protein
into an insoluble fibrin clot (tested in the in vitro thrombin
time [TT]).

Eventually activated 13 convert unstable fibrin clot to stable

clot

- Removal of the clot by fibrinolysis.

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 DIFFERENTIAL DIAGNOSIS OF BLEEDING DISORDERS
Vascular lesions:
Usually produce palpable purpura
- Hereditary: hereditary hemorrhagic telangiectasia (AD)
- Acquired:
a) Meningococcemia: life threatening emergency condition

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 b) IgA vasculitis (Henoch-Schönlein purpura)

c) Other systemic CT diseases e.g., HHT, scurvy,

corticosteroids, SLE,
Platelet defects:
Thrombocytopenia:
Definition – Thrombocytopenia is defined as a platelet count
<150,000/microL. It is clinically suspected when there is a history of easy
bruising or bleeding, or it may present as an incidental finding during
routine evaluation
Causes of platelet destruction –
• Immune-mediated destruction including
a) immune thrombocytopenia [ITP]) (refer to topic).
b) Evans syndrome refers to autoimmune thrombocytopenia and
autoimmune hemolytic anemia
c) systemic autoimmune diseases e.g., SLE, autoimmune
hepatitis, autoimmune hypothyroidism
d) Drug-induced thrombocytopenia e.g. heparin (heparin
induced thrombocytopenia), valproic acid, cotrimoxazole,
vancomycin
• Non-Immune-mediated destruction including
a) Disseminated intravascular coagulation (DIC)

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 b) Hemolytic uremic syndrome (HUS)
c) Kasabach-Merritt phenomenon, in association with large giant
hemangioma
d) Mechanical platelet destruction e.g. extracorporeal
membrane oxygenation and cardiopulmonary bypass)
e) hypersplenism
Causes of impaired platelet production:
• acquired
a) Infection e.g. bacterial sepsis, HIV, Epstein-Barr virus,
cytomegalovirus, parvovirus
b) Bone marrow infiltration e.g., Leukemia, lymphoma
c) Aplastic anemia
• genetic
a) Congenital amegakaryocytic thrombocytopenia
b) Thrombocytopenia absent radius (TAR syndrome)
c) Fanconi anemia: genetic bm failure associated with
chromosomal breakage and physical features e.g. short
stature, café au lit patches, microcephaly.
d) Wiskott-Aldrich syndrome (WAS): XLR disorder in which there
is thrombocytopenia+ small platelets+ immune deficiency+
chronic eczema

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 e) Bernard-Soulier syndrome: AR disorder with mild
thrombocytopenia+ giant platelets+ mucocutaneous bleeding.
Due to deficiency of surface GP1b receptor for VWF
Platelet function disorders:
d) Acquired causes: are much more common than inherited
causes and include use of certain medications (eg, aspirin
nonsteroidal antiinflammatory drugs [NSAIDS]), uremia.
e) inherited disorders of platelet function are relatively rare
and include:
- Glanzmann thrombasthenia – Characterized by a defect in
the platelet glycoprotein IIb/IIIa complex
- Bernard-Soulier syndrome – Characterized by a defect in
platelet glycoprotein Ib, giant platelets, and bleeding that is
greater than expected for the degree of thrombocytopenia
- platelet granule deficiency: e.g., Hermansky-Pudlak
syndrome and Chediak-Higashi syndrome
N.B. Bernard-Soulier syndrome cause both quantitative and qualitative platelet defect

Coagulation disorders
Hemophilia
a) Hemophilia A (factor 8 deficiency)
b) Hemophilia B (factor 9 deficiency)

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 c) Hemophilia C (factor 11 deficiency)
Hemophilia A and B are AR, while hemophilia C (Chrismas
disease) is AR
Acquired coagulopathy:
a) Disseminated intravascular coagulation (DIC)
b) Hepatitis
c) Hemorrhagic disease of newborn (HDN)

APPROACH TO A CHILD WITH BLEEDING

History
- The evaluation of a child with abnormal bleeding begins with a
focused history, including the clinical presentation, family
history, and medications.
- Careful attention should be paid to the child's bleeding history,
including number and severity of bleeding episodes and
characterizing the type of bleeding. The possibility of an
underlying bleeding disorder should be considered in children
who experience bleeding symptoms that are:
•Unusually frequent
•Severe
•prolonged after minor trauma or surgery e.g. tooth extraction,
circumcision

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 •from more than 1 site
•easy bruising
- Mucocutaneous bleeding into the skin and mucous membranes
e.g. epistaxis, mouth bleeding, git bleeding, menorrhagia,
hematuria, is characteristic of platelet (or vascular disorders)
disorders, while deep bleeding into muscle, joint, and soft tissue
bleeding is characteristic of coagulation disorders
- Family history — The family history is helpful in supporting a
possible diagnosis of an inherited disorder of coagulation. The
presence of bleeding manifestations only in male siblings and
maternal uncles is suggestive of an X-linked recessive disorder,
such as hemophilia A or B. Most instances of VWD are also
inherited in an autosomal dominant fashion.
- Medication history: particularly nonsteroidal antiinflammatory
drugs (NSAIDs; eg, ibuprofen, naproxen), aspirin; that produce
impaired platelet function

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 Type of bleeding disorder

Thrombocytopenia Clotting factor

Bleeding characteristics
or platelet function deficiencies or
disorders inhibitors

Major sites of bleeding Mucocutaneous Deep tissue (joints,

(prolonged epistaxis, muscles) or soft
oral bleeding, tissue hematomas
gastrointestinal
tract, urinary tract,
menorrhagia)

Petechiae Common Uncommon

Ecchymoses Easy bruising, (small May be large

and superficial) ecchymoses (deep)

bleeding after minor cuts Yes Not usually

Excessive bleeding with Often immediate Often during the

surgery or procedures e,g, procedure or after
tooth extraction, circumcision (prolonged)

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 investigations
Initial laboratory evaluation –:
a) Complete blood count (including platelet count)
b) Examination of the peripheral blood smear
c) BT (less reliable, less sensitive/less specific)
d) Prothrombin time (PT)
e) Activated partial thromboplastin time (aPTT)
f) Fibrinogen level
g) Screening tests for von Willebrand disease (VWD),
including von Willebrand factor (VWF) antigen,
VWF activity, and factor VIII activity
N.B. the first 4 tests are the basic tests
MORE SELECTIVE LABORATORY TESTS:
a) Coagulation factor assay
b) Inhibitor testing
c) Platelet function testing, by:
• PFA-100
• Aggregometry
• Flow-cytometry

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 Diagnostic approach
Abnormal blood count
a) Pancytopenia — Two important diagnostic considerations in a
child with mucocutaneous bleeding and pancytopenia include:
●Leukemia – Other concerning findings that may point to this
diagnosis include organomegaly, lymphadenopathy, and/or bone
pain. Examination of the peripheral blood smear may reveal the
presence of leukemic blasts
●Aplastic anemia – Children with aplastic anemia present with
varying combinations of
b) Thrombocytopenia — refer to causes of thrombocytopenia
c) aPTT prolonged/PT normal —
●Hemophilia A or B –
●Factor XI deficiency (hemophilia c – parahemophilia)
- PT prolonged/aPTT normal —
● Inherited factor VII deficiency
● early LCF
● Hemorrhagic disease of newborn
d) PT and aPTT both prolonged
- Well child — Inherited deficiencies in factors X, V, and II;
(prothrombin); or fibrinogen.

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 - Sick child — Disorders to consider are disseminated intravascular
coagulation (DIC; eg, due to sepsis or other systemic illness),
severe liver disease, or severe vitamin K deficiency.
e) Abnormal von Willebrand disease testing — see VWD
f) Normal initial testing — In children with bleeding symptoms and a
normal initial laboratory screen, possible diagnoses include:
- some cases of hemophilia
- Factor XIII deficiency: AR disorder
- Platelet function disorders — see before
- Vascular purpuras — see before

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Diagnostic approach using basic initial testing:

Platelet
Disorder PT aPTT BT
count

Vasculopathies e.g. normal normal normal normal

Henoch-Schönlein vasculitis

Thrombocytopenia e,g, ITP low normal normal prolonged

Platelet dysfunction normal or normal normal prolonged

(thrombasthenia) mildly low

Hemophilia A (factor VIII normal normal long normal

deficiency)

von Willebrand disease normalΔ normal normal or May be

long◊ prolonged

Disseminated intravascular low long long prolonged

coagulation

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 petichae

Superficial ecchymosis

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 COMMON SPECIFIC BLEEDING DISORDERS
Immune thrombocytopenia (ITP)
- Immune thrombocytopenia (ITP) of childhood is characterized by
isolated thrombocytopenia (platelet count <100,000/microL with
normal white blood cell count, hemoglobin, and blood smear)
- The cause of ITP remains unknown in most cases, but it can be
triggered by a viral or environmental trigger
- previously known as idiopathic thrombocytopenic purpura or
immune thrombocytopenic purpura (not anymore used terms)
clinical picture

- ITP is one of the most common causes of symptomatic

thrombocytopenia in children. Children with ITP can present at
any age, but there is a peak in incidence between two and five
years and a second smaller peak in adolescence.

- Primary ITP is categorized into three phases, depending on

duration :

a) Newly diagnosed ITP – ITP within three months from

diagnosis (ie, from the first low platelet count)

b) Persistent ITP – ITP between 3 and 12 months after diagnosis

c) Chronic ITP – ITP lasting for more than 12 months

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Bleeding manifestations:
a) ITP typically presents with the sudden appearance of a petechial
rash, bruising, and/or bleeding in an otherwise healthy child
b) 40 percent of patients also have mucosal bleeding (involving the
nasal passages, oral cavity, and genitourinary and GI tracts
c) Rarely (<1 percent), severe and life-threatening (eg, intracranial
hemorrhage [ICH], severe gastrointestinal [GI] bleeding)
d) Preceding viral illness or vaccination – Many children with ITP have
a history of preceding viral illness. ITP may also rarely occur
following measles, mumps, and rubella (MMR) vaccination.
e) Absence of systemic symptoms – Other than mucocutaneous
bleeding, patients with ITP usually appear and feel well. The
following features are generally absent :
- Systemic symptoms (eg, fever, anorexia, bone or joint pain,
weight loss…
- Exposure to thrombocytopenia-inducing drugs
- Personal or family history of thrombocytopenia and/or bleeding
- Enlargement of lymph nodes, liver, or spleen on physical
examination

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 purpura on the legs of a patient with ITP.

Investigations:
Initial laboratory tests –
- Complete blood count (CBC) with differential and rreticulocyte
count: Platelet count <100,000/micro, Otherwise normal CBC
with normal differential white count, hemoglobin, and
reticulocyte count
- Examination of the peripheral blood smear: no abnormalities
e.g., blasts
- A bone marrow examination: shows increased megakaryocytes
with defective budding; but is not routinely required in children

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 with a typical presentation and characteristic laboratory findings
of ITP (ie, isolated thrombocytopenia).
Indications for bone marrow aspiration and biopsy include:
a) atypical clinical or laboratory features at presentation,
b) new findings that emerge during follow-up that are not
consistent with ITP
c) failure to respond to ITP treatment (if given)
Treatment:
- Watchful waiting for most patients – if no or cutaneous
purpura/ecchymosis only, whatever the platelet count. Watchful
waiting consists of regular clinical assessments, serial
measurements of the platelet count, ensuring regular FU and
activity restriction.
- Pharmacological therapy: if significant bleeding (including
mucosal purpura) and include:
a) oral glucocorticoids Prednisone 4 mg/kg per day orally for 5 to
7 days
b) IV IVIG: 1 gram/kg per day IV for 1 to 3 days
c) IV Anti-D: 75 micrograms/kg IV, as a single dose; should not be
used in patients with Rh-negative blood type, positive direct
antiglobulin test (DAT), hemolytic anemia, or prior
splenectomy.

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 d) Treatment of chronic resistant ITP (more than 1 year):
Indicated if:
- Platelet count less than 10000/ul, irrespective of bleeding
- Platelet count less than 10000/ul, if activity cannot be controlled
- Significant bleeding e.g., severe epistaxis, GIT bleeding
a) Rituximab (monoclonal antibodies- anti-CD20): 375
mg/m2 weekly for 4 weeks
b) Thrombopoietin receptor agonists (eg, eltrombopag,
romiplostim)
c) Splenectomy
Disease course –
- Most children with ITP (60%) recover within three months of
presentation, with or without treatment
- About 15% recover within 12 months
- About 255 run chronic course (persistent disease more than 1
year)

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 Von Willebrand disease (VWD)
- VWF promotes platelet adhesion to endothelial cells yhrough
binding to platelet Gb1b. also it provides a carrier function to
factor 8 increasing its half life from 2 to about 12 hours.
- Von Willebrand disease (VWD) is the most common inherited
bleeding disorder. Symptomatic disease affects 1 in 1000 people.
Transmission is usually autosomal dominant. Types 2N, 3 are
autosomal recessive
There are three types
a) Type 1 (reduced von Willebrand factor [VWF]) (<30 percent is the
most common
b) Type 2 (dysfunctional VWF), includes four subtypes
- Type 2A: decreased HMW multimers
- Type 2B: decreased HMW multimers with increased platelet
binding (thrombocytopenia)
- Type 2M: normal HMW multimers
- Type 2N: decreased binging to factor 8
c) Type 3 (absent/undetectable VWF) is rare

- +ve family history is important for diagnosis

Clinical picture:
Typical bleeding include:

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 a) Easy Bruising
b) mucocutaneous bleeding e.g. bleeding from wounds,
venipuncture, prolonged epistaxis, oral bleeding
c) heavy menstrual bleeding,
d) Hemarthrosis and deep SC and muscle bleeding similar to
hemophilia occur in type 2N and type 3
Investigations:
e) BT: prolonged
f) CBC: may be mild thrombocytopenia in type 2b
g) PT: normal
h) PTT: may be prolonged in type 3
i) Screening tests for VWD include VWF antigen (VWF:Ag),
platelet-dependent VWF activity (VWF:RCo or VWF:GPIbM),
and factor VIII activity.
Platelet-dependent VWF activity or VWF:Ag <30 percent confirms
VWD.
Treatment:
j) First-degree relatives should have a thorough bleeding history
and may require testing, particularly if they have a positive
bleeding history
k) DDAVP – DDAVP is often effective in type 1 patients with minor
bleeding or minor procedures

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 l) VWF concentrates and factor VIII –in severe bleeding (all type
3, many type 2 and some type 1 patients) or if DDAVP fails to
control bleeding
m)Antifibrinolytic agents – Epsilon aminocaproic acid or
tranexamic acid reduce fibrinolysis (clot breakdown).
contraindicated in upper urinary tract bleeding.

Hemophilia
Hemophilia A (factor VIII [8] deficiency) and hemophilia B (factor IX [9]
deficiency) are heritable X-linked recessive bleeding disorders. Severity
depends largely on the factor activity level, with severe disease defined
as <1 percent of normal; moderate disease as 1 to 5 percent, and mild
disease as >5-30 percent.
Clinical picture:
a) Mostly affect males (XLR) with +ve FH from maternal side.
However, one-third of patients with hemophilia have new
mutation and negative family history
b) Bleeding in hemophilia is usually traumatic and prolonged,
however, Severe hemophilia causes spontaneous bleeding and
bleeding after minor trauma. In contrast, mild hemophilia may
only become apparent when there is significant trauma or
surgery.

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c) Hemophilia in females may be due to:
- severe hemophilia in females may be due to:
● an affected male and a female carrier
●Extreme degrees of X chromosome inactivation (lyonization)
● Turner syndrome
- bleeding in female carrier: Some females have symptoms similar
to males with mild hemophilia with factor level below 40%
d) Common presentation include:
- Bruising, usually traumatic , extensive and deep
- Prolonged bleeding after tooth extraction, circumcision
- Hemarthrosis (the commonest presentation). The patient feels
heaviness and tingling then pain and swelling in affected joint.
Recurrent bleeding in same joint (target joint) lead to joint
destruction and deformity
- Life threatening IC hemorrhage occur in 3 to 5 percent of infants
with severe hemophilia

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 Hemoarthrosis in hemophilia

Investigations:
e) BT: normal
f) CBC: normal
g) PT: normal
h) PTT: prolonged
i) Measurement of the factor activity level (factor VIII in
hemophilia A; factor IX in hemophilia B) : <40 percent
j) von Willebrand factor antigen (VWF:Ag) is normal in
hemophilia.
k) Testing for inhibitors
Complications –
a) hemophilic arthropathy: joint destruction due to repeated bleeding
(target joint affection)
b) development of antibodies to the infused factor

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 Hemophilic arthropathy

MANAGEMENT:
- Treatment of bleeding (episodic, on-demand treatment), using
plasma derived or recombinant factor concentrate
a) Serious bleeding – Serious or life-threatening bleeding
(intracranial, ocular) requires urgent treatment with factor
concentrate, targeting a factor activity of 80 to 100 percent
•Hemophilia A without an inhibitor – Give 50 units/kg of factor
VIII / 12 hours
•Hemophilia B without an inhibitor – Give 100 to 140 units/kg
of factor IX / 24 hours
•Inhibitors – treatment by recombinant factor VIIa

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b) Joint bleeding –target factor activity at approximately 50
percent (25 units/kg of factor VIII / 12 hours & 50 units/kg of
factor IX / 24 hours)
c) Desmopressin can be used in mild bleeding due to mild
hemophilia (it raise factor 8 and VWF)
d) Antifibrinolytic therapy – e.g. tranexamic acid or Epsilon
aminocaproic acid. This may be the sole therapy required (eg,
mild hemophilia, dental procedure).
- Continuous (regular) prophylaxis: Replacement factor given to
prevent bleeding for at least 45 of 52 weeks (85%) of a year:
a) Primary prophylaxis: Continuous prophylaxis started before age
three years and before the second large joint bleed
b) Secondary prophylaxis: Continuous prophylaxis started after
two or more large joint bleeds but before the onset of chronic
arthropathy
c) Tertiary prophylaxis: Continuous prophylaxis started after the
onset of arthropathy to prevent further damage
Prophylaxis is done using factor concentrate or Emicizumab
(new monoclonal ab replacing factor 8 in coagulation process)

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 Available products for factor 8 replacement:
product Factor content Approximate conc.
Of factor 8 (u/ml)
Fresh frozen plasma All clotting factors 1
cryoprecipitate Factor 8, VWF, 5-10
fibrinogen
Factor 8 Factor 8 20-25
concentrate*
Emicizumab Factor 8 substitute
*factor 8 concentrate can be either plasma derived concentrate e.g. koate or recombinant
product e.g.kogenate

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