Approach to bleeding disorder (coagulation defects) in children

Dr. Vadapalli SATISH
SMIMS, Gangtok
MD Paeds. 2nd year

A bleeding tendency is a presentation with
bleeding in a patient in whom no anatomical
cause for the bleeding (i.e., trauma to a
vessel for one of many possible reasons) can
be discovered.
 It is then inferred that the bleeding is due to
a functional impairment of the normal
hemostatic process.

This impairment may be due to

1. A functional deficiency in the procoagulant
mechanism. This may involve
a. The platelets
b. The procoagulant plasma components

2. A functional excess in anticoagulant
mechanisms.
a. Anticoagulant drugs
b. Natural anticoagulants

3. A functional excess in the fibrinolytic
mechanism.

 Broadly we can identify three types:

 „„COAGULATION-DEFECT BLEEDS,‟‟
 „„PURPURIC-TYPE BLEEDS,‟‟ and
 MIXED bleeds.

 Localized cyanosis is differentiated from
ecchymosis by the momentary blanching
pallor (with cyanosis) occurs after pressure

Finding Disorders of Disorders of
Coagulation Platelets or Vessels
Petechiae Rare Characteristic
Deep dissecting Characteristic Rare
hematomas
Superficial Common; usually Characteristic;
ecchymoses large and usually small and
solitary multiple
Hemarthrosis Characteristic Rare
Delayed bleeding Common Rare
Bleeding from Minimal Persistent often profuse
superficial cuts and
scratches
Sex of patient 80–90% of inherited Relatively more
forms occur only in common in females
male patients
Positive family Common Rare (exc. vWF ,
history hereditary hemorr.
telangiectasia)

Table 118–1. Classification of Disorders of Hemostasis

Major Types Disorders Examples
Acquired Thrombocyto Autoimmune and alloimmune, drug-induced,
penias hypersplenism, hypoplastic (primary,
myelosuppressive therapy, myelophthisic marrow
infiltration), disseminated intravascular
coagulation (DIC), thrombotic thrombocytopenic
purpura, hemolytic-uremic syndrome

Liver diseases Cirrhosis, acute hepatic failure, liver
transplantation (see Chap. 129), thrombopoietin
deficiency
Renal failure
Vitamin K Malabsorption syndrome, hemorrhagic disease of
deficiency the newborn, prolonged antibiotic therapy,
malnutrition, prolonged biliary obstruction
Hematologic Acute leukemias (particularly promyelocytic),
disorders myelodysplasias, monoclonal gammopathies,
essential thrombocythemia

Acquired Acquired Neutralizing antibodies against factors V, VIII,
antibodies and XIII, accelerated clearance of antibody-
against factor complexes, e.g., acquired von
coagulation Willebrand disease, hypoprothrombinemia
factors associated with antiphospholipid antibodies
DIC Acute (sepsis, malignancies, trauma, obstetric
complications) and chronic (malignancies, giant
hemangiomas, retained products of conception)

Drugs Antiplatelet agents, anticoagulants,
antithrombins, and thrombolytic, hepatotoxic,
and nephrotoxic agents
Vascular Nonpalpable purpura ("senile," solar, and
factitious purpura), use of corticosteroids,
vitamin C deficiency, child abuse,
thromboembolic, purpura fulminans; palpable-
purpura (Henoch-Schönlein, vasculitis,
dysproteinemias; amyloidosis

Table 118–1. Classification of Disorders of Hemostasis

Inherited Deficiencies of Hemophilia A (factor VIII deficiency),
coagulation hemophilia B (factor IX deficiency),
factors deficiencies of fibrinogen factors II, V,
VII, X, XI, and XIII and von Willebrand
disease
Platelet Glanzmann thrombasthenia, Bernard-
disorders Soulier syndrome, platelet granule
disorders
Fibrinolytic 2-Antiplasmin deficiency, plasminogen
disorders activator inhibitor-1 deficiency
Vascular Hemorrhagic telangiectasias
Connective Ehlers-Danlos syndrome
tissue disorders

 1.Patients vary in their responses to
hemorrhagic symptoms.
 Therefore, some experts believe the question
"Do you bruise easily?" is virtually worthless.
Women more likely respond that they have
excessive bleeding or bruising than do men.

 2. Unprovoked hemarthroses and muscle
hemorrhages suggest one of the hemophilias.
 mucocutaneous bleeding (epistaxis, gingival
bleeding, menorrhagia) are more
characteristic of patients with qualitative
platelet disorders, thrombocytopenia, or von
Willebrand disease.

 3. Assessing the extent of hemorrhage
against the background of any trauma or
provocation that may have elicited the
hemorrhage is important.
 If a patient has never had a significant
hemostatic challenge (such as tooth
extraction, surgery, trauma, or childbirth),
the lack of a significant bleeding history is
much less valuable in excluding a mild
hemorrhagic disorder.

 4. Obtaining objective confirmation of the
subjective information conveyed in the
bleeding history is valuable.
 Objective data include
 (a) previous hospital or physician visits for
bleeding symptoms,
 (b) results of previous laboratory
evaluations,
 (c) previous transfusions of blood products
for bleeding episodes, and
 (d) a history of anemia and/or previous
treatment with iron.

 5. A medication history esp. non-prescription
drugs.
 A medication history is especially important
in patients with thrombocytopenia, because
drug-induced thrombocytopenia is common.
 Medication also may affect hemostasis
through deleterious effects on the liver or
kidney functions.

 Herbal and alternative medicines poses
particular problems, because patients may
not readily share information about the drug
and the dose they are taking of any
particular active ingredient may be difficult
to determine.
 Ginkgo biloba and ginseng are the most
commonly used herbals that can cause
platelet dysfunction and induce bleeding.
 Other dietary supplements.

 6. A nutrition history should be obtained to
assess the likelihood of
 (a) vitamin K deficiency, especially if the
patient also is taking broad-spectrum
antibiotics,
 (b) vitamin C deficiency, especially if the
patient has skin bleeding consistent with
scurvy (perifollicular purpura), and
 (c) general malnutrition and/or
malabsorption.

 7. Several tissues have an increased local
fibrinolytic activity.
 urinary tract,
 endometrium, and
 mucous membranes of the nose and oral
cavity.
 These sites are particularly likely to have
prolonged oozing of blood after trauma in
patients with hemostatic abnormalities.
Excessive bleeding following tooth extraction
is one of the most common manifestations.

 8.Bleeding isolated to a single organ or
system (e.g., hematuria, hematemesis,
melena, hemoptysis) is less likely to result
from a hemostatic abnormality than from a
local cause such as neoplasm, ulcer, or
angiodysplasia. Thus, careful anatomic
evaluation of the involved organ or system
should be performed.

 9.Bleeding may result from blood vessel
disorders such as hereditary hemorrhagic
telangiectasias, Cushing disease, scurvy, or
Ehlers-Danlos syndrome. Many primary
dermatologic disorders also have a purpuric
or hemorrhagic component and must also be
considered in the differential diagnosis.

 10. A family history is particularly important
when hereditary disorders are considered.
 consanguinity,
 genealogic tree, extending back at least two
generations for genetic disorders.
 A sex-linked pattern hemophilia A or B
 An AD, most forms of vWD
 An AR, coagulation factor deficiencies,
inherited platelet disorders, and the rare,
severe, type 3 von Willebrand disease.

 11.Population genetic information may be
helpful; for example, the higher prevalence
of factor XI deficiency in Ashkenazi Jews

 12.Diseases and organs that may affect
hemostasis, such as cirrhosis, renal
insufficiency, myeloproliferative disorders
(e.g., essential thrombocythemia), acute
leukemia, myelodysplasia, systemic lupus
erythematosus, and Gaucher disease.

Table 118–2. Clinical Manifestations Typically Associated with
Specific Hemostatic Disorders

Clinical Manifestations Hemostatic Disorders
Mucocutaneous bleeding Thrombocytopenias, platelet
dysfunction, von Willebrand disease
Cephalhematomas in Severe hemophilias A and B, severe
newborns, hemarthroses, deficiencies of factor VII, X, or XIII,
hematuria, and intramuscular, severe type 3 von Willebrand disease,
intracerebral, and afibrinogenemia
retroperitoneal hemorrhages
Injury-related bleeding and Mild and moderate hemophilias A and B,
mild spontaneous bleeding severe factor XI deficiency, moderate
deficiencies of fibrinogen and factors II,
V, VII, or X, combined factors V and VIII
deficiency, 2-antiplasmin deficiency

Table 118–2. Clinical Manifestations Typically Associated with
Specific Hemostatic Disorders

Bleeding from stump of Afibrinogenemia, hypofibrinogenemia,
umbilical cord and habitual dysfibrinogenemia, factor XIII deficiency
abortions
Impaired wound healing Factor XIII deficiency
Facial purpura in newborns Glanzmann thrombasthenia, severe
thrombocytopenia
Recurrent severe epistaxis Hereditary hemorrhagic telangiectasias
and chronic iron deficiency
anemia

 1. Epistaxis is one of the most common
symptoms of platelet disorders & vWD.
 It also is the most common symptom of
hereditary hemorrhagic telangiectasia.
epistaxis - more severe with advancing age.
 Epistaxis is not uncommon in normal
children, usu. resolves before puberty.
 Dry air heating systems can provoke epistaxis
even in normal individuals. Bleeding confined
to a single nostril - local vascular problem
than a systemic coagulopathy.

 2. Gingival hemorrhage is very common in
patients with both qualitative and
quantitative platelet abnormalities and von
Willebrand disease.
 Occasional gum bleeding occurs in normal.
 3. Oral mucous membrane bleeding in the
form of blood blisters is a common
manifestation of severe thrombocytopenia.
Such bleeding usually has a predilection for
sites where teeth can traumatize the inner
surface of the cheek.

 4. Skin hemorrhage in the form of petechiae
and ecchymoses are common manifestations
of hemostatic & non-hemostatic disorders.
 Excessive bruising is more common in women
than men.
 Bruising varies with the phase of their
menstrual cycle.
 Severity of skin hemorrhage include the size,
the frequency, spontaneously or only with
trauma, and bruises on non traumatized
regions, such as the trunk and back.

 5. The color of the bruise
 Red bruises on the extensor surfaces of the
arms and hands indicate loss of supporting
tissues, as occurs in Cushing syndrome,
glucocorticoid therapy, senile purpura, and
damage from chronic sun exposure.
 Jet-black bruises-warfarin induced skin
necrosis.

 Easybruising can also occur in patients with
Ehlers-Danlos syndrome manifested by
distensible skin or extraordinary ligament
laxness, and in patients with hyperflexibility
of the thumb.

 6.Tooth extractions - helpful in defining the
risk of bleeding. Molar extractions >>
extractions of other teeth.
 Objective data regarding excessive bleeding
based on the need for blood products or the
need to pack or suture the extraction site
are valuable.
 7. Excessive bleeding in response to razor
nicks is common in patients with platelet
disorders or von Willebrand disease.

 8. Hemoptysis- never a bleeding disorder and
is rare even in patients with serious bleeding
disorders.
 However, blood-tinged sputum in association
with upper respiratory tract infections may
be more common in patients with hemostatic
disorders.

 9. Hematemesis- never a hemostatic
disorder. However, a hemostatic disorder may
lead to hematemesis because of an anatomic
abnormality in the upper gastrointestinal
tract.
 Some hemostatic disorders more likely result
in hematemesis because of a combination of
effects, such as liver disease with deficient
synthesis of coagulation proteins and with
esophageal varices and aspirin ingestion with
gastritis.

 10. Hematuria-rarely presenting c/o -exc. for
the hemophilias.
 However, hemostatic disorders-exacerbate
hematuria caused by other disorders,eg. UTI.
 11. Rectal bleeding-in normal-hemorrhoids.
 von Willebrand disease and platelet disorders
- associated with a number of different
underlying causes, including diverticuli,
hemorrhoids, or angiodysplasia.
 Melena-rarely the presenting symptom. But,
repeated episodes-hemor. disorders.

 12. Menorrhagia is common in women with
platelet disorders and von Willebrand
disease. In general, menstrual bleeding is
considered excessive if the patient indicates
she has heavy flow for more than 3 days or
total flow for more than 7 days.
 objective distinction b/w menorrhagia (loss
of more than 80 mL blood per period) and
normal blood loss can only be made by a
visual assessment technique using pictorial
charts of towels or tampons.

 13. Postpartum hemorrhage- bleeding
disorders commonly manifest excessive
bleeding during or after labor necessitating
blood transfusion.
 14. Habitual spontaneous abortions raise the
possibility that the patient has a quantitative
or qualitative abnormality of fibrinogen,
factor XIII deficiency, or the antiphospholipid
syndrome.

 15.Hemarthroses are the hallmark
abnormality in the hemophiliac; severe
factor VII deficiency and type 3 von
Willebrand disease
 patients may not recognize that their
symptoms (pain, swelling, and limitation of
motion) are caused by bleeding into their
joints.

 16.Excessive hemorrhage associated with
surgical procedures is common in patients
with hemorrhagic disorders. Procedures
involving tissues with increased local
fibrinolytic activity like urinary tract, nose,
tonsils and oral cavity are particularly prone
to bleed.

 17. Excessive bleeding following circumcision
is common in males with severe hemostatic
disorders such as hemophilia A, hemophilia
B, or Glanzmann thromboasthenia, and often
is the patient's first symptom.
 18. Bleeding from the umbilical stump is
characteristic of factor XIII deficiency and
afibrinogenemia.

 PT measures – THE EXTRINSIC PATHWAY
 PT is prolonged with deficiencies of factors
VII, V, X, II, I.
 In most laboratories, the normal PT value is
10-13 sec. PT has been standardized using
the International Normalized Ratio (INR) so
that values can be compared from 1
laboratory or instrument to another. This
ratio is used to determine similar degrees of
anticoagulation with warfarin (Coumadin)–
like medications.

 This test measures the – INTRINSIC PATHWAY-
initiation of clotting at the level of factor XII
through sequential steps to the final clot
end-point.
 In vivo, activation of factor XII, by
prekallikrein and HMWK.
 In lab, factor XII is activated using a surface
(silica or glass) or a contact activator, such as
ellagic acid.

 Factor XIIa => factor XI - XIa, => factor IX to
factor IXa. On the platelet phospholipid
surface, factor IXa complexes with factor VIII
and calcium to activate factor X
(“tenase”complex).
 accelerated by interaction with phospholipid
and calcium, involving factors V and VIII.

 An isolated deficiency of a single clotting
factor may result in isolated prolongation of
PT, PTT, or both, depending on the location
of the factor in the clotting cascade.
 This approach is useful in determining
hereditary clotting factor deficiencies;
however, in acquired hemostatic disorders
encountered in clinical practice, > 1 clotting
factor is frequently deficient, so the relative
prolongation of PT and PTT must be
assessed.

 Normal ranges for PTT are much more
variable from laboratory to laboratory than
those for PT.
 Thus, the mechanisms studied by PT and PTT
allow the evaluation of clotting factor
deficiencies, even though these pathways
may not be the same as those occurring
physiologically.

 In vivo, factor VIIa activates factors IX and X,
 Lab.- factor VIIa => factor X only.
 This explain why the most severe bleeding
disorders are hemophilias factor VIII & IX.
 In vivo, II feeds back to XI and accelerate the
clotting process.
 PTT can be prolonged by deficiencies of
factor XII, prekallikrein, and HMWK, yet NO
BLEEDING.

 Ifprolong. PT, PTT, or TT=> a mixing study.
 Normal plasma is added to the patient's
plasma, and the PT or PTT is repeated.
 Correction of PT or PTT => def. of a clotting
factor, (because a 50% level of individual
clotting proteins is sufficient to produce
normal PT or PTT.)

 Ifthe clotting time is not corrected or only
partially corrected, an inhibitor is usually
present.
 An inhibitor of clotting may be -
 -either a chemical similar to heparin that
delays coagulation
 -or an antibody directed against a specific
clotting factor.(MC- VIII, IX, or XI, may be
present).
 -or the phospholipid used in clotting tests.

 In the inpatient setting, the most common
cause of this finding is heparin contamination
of the sample. The presence of heparin in
the sample can be ruled in or out with the
use of thrombin time and reptilase time.

 Ifno bleeding and both PTT and the mixing
study are prolonged, a lupus-like
anticoagulant is often present.(clinical
predisposition to excessive clotting)

Prolongation of thrombin time occurs in-
-reduced fibrinogen levels
(hypofibrinogenemia or afibrinogenemia).
-dysfunctional fibrinogen
(dysfibrinogenemia), or
-the use of substances that interfere with
fibrin polymerization, such as heparin or
fibrin split products.

 TT measures the final step in the clotting
cascade, (fibrinogen => fibrin). The normal
TT is usu. 11–15 sec.
 In heparin contamination, RT is usually
ordered.

 RT uses snake venom to clot fibrinogen.
 Unlike TT, RT is not sensitive to heparin
 RT is inc. only by reduced or dysfunctional
fibrinogen and fibrin split products.
 If TT is inc and RT is N = Heparin (not
reduced concentration or function of
fibrinogen)

 Bleeding time assesses the function of
platelets and their interaction with the
vascular wall.
 Disposable standardized devices have been
developed that control the length and depth
of the skin incision. A blood pressure cuff is
applied to the upper arm and inflated to 40
mm Hg for children and adults. In term
newborns and younger children, a modified
device has been developed that is used with
a lower blood pressure cuff pressure.

 After an incision is made with the bleeding
time device, blood is blotted from the
margin of the incision at 30-sec intervals
until bleeding ceases.
 usually stops within 4-8 min.
 Bleeding time is a difficult laboratory test to
standardize, and there is much
interlaboratory and interindividual variation.
 prolonged bleeding time, qualitative platelet
defect or VWD, PLC< 1 lakh/cu.mm

 Essentials of Diagnosis & Typical
Features
 -Easy bruising and epistaxis from early
childhood.
 -Menorrhagia.
 -Prolonged PFA-100 (or bleeding time);
normal platelet count; absence of acquired
platelet dysfunction.
 -Reduced activity or abnormal structure of
vWF.

 the most common inherited bleeding disorder
among Caucasians, with a prevalence of 1%.
vWF is a protein present as a multimeric
complex in plasma, which binds factor VIII
and is a cofactor for platelet adhesion to the
endothelium.
 An estimated 70–80% - classic vWD (type 1) -
partial quantitative deficiency of vWF.
 vWD type 2 involves a qualitative deficiency
of (ie, dysfunctional) vWF, and
 vWD type 3 - nearly complete deficiency of
vWF.

 The majority (> 80%) with type 1 disease are
asymptomatic. vWD is most often
transmitted as AD trait, but can be AR.
 The disease can also be acquired, developing
in association with hypothyroidism, Wilms
tumor, cardiac disease, renal disease, or
systemic lupus erythematosus and in
individuals receiving valproic acid. Acquired
vWD is most often caused by the
development of an antibody to vWF or
increased turnover of vWF.

A history of increased bruising and excessive
epistaxis is often present. Prolonged bleeding
also occurs with trauma or at surgery.
Menorrhagia is often a presenting finding in
females.

 PT is normal, and aPTT is sometimes prolonged.
 Prolongation of the PFA-100 or bleeding time is
usually present since vWF plays a role in platelet
adherence to endothelium.
 Dec PLC in type 2b vWD.
 Factor VIII and vWF antigen are decreased in
types 1 and 3, but may be normal in type 2 vWD.
 vWF activity (eg, ristocetin cofactor or collagen
binding) is decreased in all types.
 BGT important - normal vWF antigen levels.( O
has least levels)
 vWF multimer assay- complete classification

 The treatment to prevent or halt bleeding
for most patients with vWD types 1 and 2 is
desmopressin acetate, release of vWF from
endothelial stores.
 Desmopressin may IV / Intranasal.
 Because response to vWF is variable among
patients, factor VIII and vWF activities are
typically measured before and 60 minutes
after infusion.

 Desmopressin may cause fluid shifts,
hyponatremia, and seizures in children
younger than 2 years of age.
 Tachyphylaxis- limited stores.
 vWF-replacement therapy (eg, plasma-
derived concentrate) is recommended;
Antifibrinolytic agents (eg, -aminocaproic
acid) , Topical thrombin and fibrin glue may
be useful for control of mucosal bleeding.
 Estrogen-OCP-for menorrhagia.

 desmopressin via release of endothelial
stores of factor VIII and vWF into plasma
 exogenous factor VIII. The in-vivo half-life of
factor VIII is generally 8–12 hours.
 Non–life-threatening, non–limb-threatening
hemorrhage is treated initially with 20–30
U/kg of factor VIII- rise in plasma factor VIII
activity to 40–60%.
 Large joint hemarthrosis and life- or limb-
threatening hemorrhage is - 50 U/kg.
 Prophylactic factor VIII infusions (eg, two or
three times weekly)

 Withthe availability of effective treatment
and prophylaxis for bleeding, life expectancy
in vWD is normal.

Comparison of vWD and Hemophilias

Hemophilia A Hemophilia B von Willebrand Disease
Factor VIII Low Normal Low or normal
coagulant
activity
von Willebrand Normal Normal Low
factor antigen
von Willebrand Normal Normal Low
factor activity
Factor IX Normal Low Normal
Ristocetin- Normal Normal Normal, low, or increased
induced platelet at low-dose ristocetin
agglutination
Platelet Normal Normal Normal
aggregation
Treatment DDAVP* or Recombinant IX
recombinant VIII

 Essentials of Diagnosis & Typical Features
 Bruising, soft-tissue bleeding, hemarthrosis.
 Prolonged activated partial thromboplastin
time (aPTT).
 Reduced factor VIII activity.

 General Considerations
 Factor VIII activity is reported in units per
milliliter, with 1 U/mL equal to 100% of the
factor activity found in 1 mL of normal
plasma. The normal range for factor VIII
activity is 0.5–1.5 U/mL (50–150%).
Hemophilia A occurs predominantly in males
as an X- linked disorder. One third of cases
are due to a new mutation. The incidence of
factor VIII deficiency is 1:5000 male births.

 severe hemophilia A (< 1% plasma factor VIII
activity) spontaneous bleeding episodes
involving skin, mucous membranes, joints,
muscles, and viscera.
 Those with moderate hemophilia A (1% to <
5% factor VIII activity) typically have
intermediate bleeding manifestations
 mild hemophilia A (5–40% factor VIII activity)
bleed only at times of trauma or surgery.
 recurrent hemarthroses that incite joint
destruction.

 prolonged aPTT, (PT) is normal.
 Diagnostic- decreased factor VIII activity with
normal vWF activity.
 In 2/3rds of families of hemophilic patients, the
females are carriers and some are mildly
symptomatic.
 Carriers of hemophilia can be detected by
determination of the ratio of factor VIII activity
to vWF antigen and by molecular genetic
techniques. In a male fetus or newborn with a
family history of hemophilia A, cord blood
sampling for factor VIII activity is accurate and
important in subsequent care.

 Intracranial hemorrhage.
 Hemarthroses begin early in childhood- joint
destruction (ie, hemophilic arthropathy).
 Large intramuscular hematomas - compartment
syndrome with resultant muscle and nerve
death.
 A serious complication - acquired circulating
antibody to factor VIII after treatment with
factor VIII concentrate. 15–25% of patients with
severe hemophilia A, - desensitization -
immunosuppressive therapy
 recombinant factor VIIa has become a therapy of
choice.

 infection with the human immunodeficiency
virus (HIV), hepatitis B virus (HBV), and
hepatitis C virus (HCV).
 Inactivation methods do not eradicate viruses
lacking a lipid envelope, however, so that
transmission of parvovirus and hepatitis A
remains a concern with the use of plasma-
derived products.
 Immunization with hepatitis A and hepatitis B
vaccines is recommended for all hemophilia
patients

 Factor XI deficiency is an AD, with mild to
moderate bleeding symptoms. It is frequently
encountered in Ashkenazi Jews but has been
found in many other ethnic groups. In
Israel,1-3/1,000 individuals are homozygous
for this deficiency.
 The bleeding tendency is not as severe and
not correlated with the amount of factor XI.
 Some patients with severe deficiency may
have minimal or no symptoms at the time of
major surgery.

 Because factor XI => + thrombin => +
fibrinolytic inhibitor TAFI , surgical bleeding
is more prominent in sites of high fibrinolytic
activity like the oral cavity.
 Unless the patient previously had surgery
without bleeding, replacement therapy
should be considered and given
preoperatively, depending on the nature of
the surgical procedure. No approved
concentrate of factor XI is available in the
USA; therefore, the physician must use fresh
frozen plasma (FFP).

 Bleeding during minor surgery can be controlled
with local pressure. Patients undergoing dental
extractions can be monitored closely and may
benefit from treatment with fibrinolytic
inhibitors like aminocaproic acid, with plasma
replacement therapy used only if hemorrhage
occurs. In a patient with homozygous deficiency
of factor XI, PTT is often longer than it is in
patients with either severe factor VIII or factor
IX deficiency.
 Chronic joint bleeding is rarely a problem in
factor XI deficiency, and for most patients, the
deficiency is a concern only at the time of major
surgery unless there is a second underlying
hemostatic defect (e.g.,von Willebrand disease)

 The paradox of fewer clinical symptoms in
combination with longer PTT is surprising,
but it occurs because factor VIIa can activate
factor IX in vivo.
 Diagnostic- specific factor XI assays.
 Plasma infusions of 1 IU/kg usually increase
the plasma concentration by 2%. Thus,
infusion of plasma at 10-15 mL/kg will result
in a plasma level of 20-30%,which is usually
sufficient to control moderate hemorrhage.
 half-life of factor XI is usually ≥48 hr,

 Deficiency of the “contact factors” (factor
XII, prekallikrein, and high molecular weight
kininogen) causes prolonged PTT but no
bleeding symptoms.
 the paradoxical situation in which PTT is
extremely prolonged with no evidence of
clinical bleeding.
 they do not need treatment, even for major
surgery.

 Factor VII deficiency is a rare autosomal
bleeding disorder- detected only in homozygous.
 Severity of bleeding varies from mild to severe
with hemarthroses, spontaneous intracranial
hemorrhage, and mucocutaneous bleeding,
especially nosebleeds and menorrhagia.
 markedly prolonged PT,normal PTT,& dec Factor
VII assays.
 Because the plasma half-life of factor VII is 2-4
hr, therapy with FFP is difficult and is often
complicated by fluid overload.
 A commercial concentrate of recombinant factor
- not approved by the FDA yet.

 Factor X deficiency is a rare (estimated
1/1,000,000) autosomal disorder with
variable severity.
 Mild deficiency -mucocutaneous and post-
traumatic bleeding, severe deficiency -
hemarthroses and intracranial hemorrhages.
 Factor X deficiency is the result of either a
quantitative deficiency or a dysfunctional
molecule.
 prolongation of both PT and PTT.

 Rx-FFP or prothrombin complex concentrate.
The half-life of factor X is approximately 30
hr, and its volume of distribution is similar to
that of factor IX. Thus, 1 U/kg will increase
the plasma level of factor X by 1%.
 rarely, systemic amyloidosis-X deficiency,
 adsorption of factor X on amyloid protein.
 transfusion therapy often is not successful
because of the rapid clearance of factor X.

 By reduced prothrombin level
(hypoprothrombinemia) , or
 by functionally abnormal prothrombin
(dysprothrombinemia).
 Laboratory testing in homozygous patients
shows prolonged PT and PTT. Factor II, or
prothrombin, assays show a markedly
reduced prothrombin level. Mucocutaneous
bleeding in infancy and post-traumatic
bleeding later are common.

 Rx- FFP or, rarely, prothrombin complex
concentrates. FFP is useful, because the
half-life of prothrombin is 3.5 days.
 Administration of 1 IU/kg of prothrombin will
increase the plasma activity by 1%.

 autosomal recessive, mild to moderate
bleeding disorder that has also been termed
parahemophilia.
 mucocutaneous bleeding and hematomas MC
symptoms. Severe menorrhagia is a frequent
symptom in women. Hemarthroses occur
rarely.
 Lab- prolonged PTT and PT. Specific assays
for factor V show a reduction.
 FFP is only option. V is lost rapidly from
stored FFP.

 Patients with severe factor V deficiency are
treated with infusions of FFP at 10 mL/kg
every 12 hr.
 Rarely, acquired antibody to factor V . Such
pt. does not bleed because the factor V in
platelets prevents excessive bleeding.

 secondary to the absence of an intracellular
transport protein that is responsible for
transporting factors V and VIII from the
endoplasmic reticulum to the Golgi
compartments.
 paradoxical deficiency of 2 factors, one
encoded on chromosome 1and X
chromosome. Bleeding symptoms are often
milder than for hemophilia A .
 Rx- FFP to replace both factors V and VIII.

 rare autosomal recessive disorder in which
there is an absence of fibrinogen.
 do not bleed as frequently as hemophiliacs,
rarely have hemarthroses.
 neonatal period with GI hemorrhage or
hematomas after vaginal delivery.
 marked prolongation of PT and PTT, thrombin
time .
 an unmeasurable fibrinogen level is
diagnostic.

 dysfunctional fibrinogens have been reported
(dysfibrinogenemia). present with
thrombosis.
 half-life of fibrinogen is 2-4 days, treatment
with either FFP or cryoprecipitate is
effective.
 Fibrinogen are inhibited by high doses of
heparin. Prolonged reptilase time confirms
that functional levels of fibrinogen are low
and that heparin is not present.

 Because factor XIII is responsible for the
cross linking of fibrin to stabilize the fibrin
clot, symptoms of delayed hemorrhage are
secondary to instability of the clot.
 Typically, patients have trauma 1 day and
then have a bruise or hematoma the next
day. Clinical symptoms include mild bruising,
delayed separation of the umbilical stump
beyond 4 wk in neonates, poor wound
healing, and recurrent spontaneous abortions
Rare hemarthroses and intracranial
hemorrhage have been described.

 PT, PTT, TT, BT are Normal
 there is increased solubility of the clot
because of the failure of cross linking. The
normal clot remains insoluble in the
presence of 5M urea, whereas in a patient
with XIII deficiency, the clot dissolves.
 More specific assays for factor XIII a.
 half-life of factor XIII is 5-7 days and the
hemostatic level is 2-3% activity, infusion of
FFP or cryoprecipitate will correct the
deficiency.

 Deficiency of either antiplasmin or
plasminogen activator inhibitor, both of
which are antifibrinolytic proteins=>
increased plasmin => premature lysis of
fibrin clots.
 mild bleeding disorder, mucocutaneous
bleeding but rarely have joint hemorrhages.
 usual hemostatic tests are normal+ positive
bleeding history => euglobulin clot lysis time,
which measures fibrinolytic activity =
shortened result.

 Specificassays for α2-antiplasmin and
plasminogen activator inhibitor are available.
 Bleeding episodes are treated with FFP;
bleeding in the oral cavity may respond to
aminocaproic acid

 The clinical phenotype of severe protein C
deficiency in neonatal purpura fulminans implies
that APC exerts multiple physiologically essential
activities, including potent anticoagulant and
anti-inflammatory actions .
 Recent advances establish that APC's
antiinflammatory actions are but one
manifestation of its ability to interact directly
with cell receptors to provide multiple
cytoprotective activities. These two distinct
types of activities of APC, intravascular
anticoagulant activity and initiation of cell
signaling, are mediated by different sets of
molecular interactions, and both types of
activities are clinically relevant.

Component Content Indication Dose Outcome expectd
Fresh frozen 1unit/mL Multiple clotting 10-15 mL/kg Improvement in
plasma of each factor deficiency prothrombin and
clotting partial
factor thromboplastin
times
Cryoprecipit Fibrinoge Hypofibrinogene 1 bag/5 kg ↑ Fibrinogen by
ate n, factor mia, factor XIII 50-100 mg/dL
VIII, vWF, deficiency
factor XIII
Recombinant Units as Hemophilic F VIII: 20-50 FVIII: 2%/unit/kg
factor labeled bleeding or units/kg* FIX: 0.7/unit/kg
concentrates prophylaxis
F IX: 40-120
units/kg*
Recombinant μg Hemophilic 90 μg/kg q3 h Cessation of
factor VIIa bleeding in bleeding
(NovoSeven) inhibitor patient;
uncontrolled post
operative
hemorrhage

Comparison of vWD and Hemophilias
Hemophilia A Hemophilia B von Willebrand Disease
Inheritance X-linked X-linked Autosomal dominant
Factor deficiency Factor VIII Factor IX von Willebrand factor and
VIIIC
Bleeding site(s) Muscle, joint, Muscle, joint, Mucous membranes, skin,
surgical surgical surgical, menstrual
Prothrombin time Normal Normal Normal
Activated partial Prolonged Prolonged Prolonged or normal
thromboplastin
time
Bleeding time Normal Normal Prolonged or normal

1. In hematology – we cant do without blood
test.
2. Only Blood test are not enough.

 A 15-year-old boy with chronic strep throat has
presented with excessive bruising. His
coagulation results were as follows:
 PT 15.5 seconds (Reference range, 10.8 to 13.5)
 aPTT 42.1 seconds (Reference range, 28.5 to
35.5)
 Platelets 325,000 (Reference range, 150,000 to
400,000)
 Bleeding 5 minutes (Reference, 8 minutes)
 Which coagulation tests are abnormal, and how
should this physician proceed in his treatment of
this patient?

 In this case, two parameters, the PT and aPTT,
are elevated. The patient is not bleeding, but he
shows a history of recent bruising. Since both the
PT and the aPTT are affected, one can assume
the problem is in the common pathway,
speciﬁcally factors I, II, V, and X.
 Factor assays could be performed to assess the
level of activity of each of these clotting factors;
 however, a closer examination into the patient‟s
history might reveal an additional feature. Since
this patient has had chronic strep throat, it is
logical to assume that he has been on long-term
antibiotics.

 Antibioticsmay deplete the normal ﬂora, a
source of vitamin K synthesis. Factors II, VII,
IX, and X are vitamin K–dependent factors.
Vitamin K is the essential cofactor for the
gamma carboxyglutamic acid residues
necessary to activate these factors. When
vitamin K is in short supply or depleted,
these factors fail to function properly. In our
patient, vitamin K can be given by mouth to
resume normal coagulation and correct
bruising.

Approach to bleeding disorder (coagulation defects) in children

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