BLEEDING

TENDENCY
Dr. Mouroge Al-
Ani
 Bleeding

disorders
Vascular Platelet Clotting factor
DIC
abnormalities disorders
abnormalities
Introduction
• Note: Blood consists of the cellular elements and plasma, which
includes the coagulation factors (13)
• Bleeding, technically known as hemorrhaging, is the loss of
blood escaping from the circulatory system.
• Bleeding can occur internally, where blood leaks from blood
vessels inside the body, or externally, either through a natural
opening such as the mouth, nose, ear, urethra, vagina or anus,
or through a break in the skin.
• Bleeding arises due to either traumatic injury, underlying
medical condition, or a combination.
• 'Medical bleeding' denotes hemorrhage as a result of
an underlying medical condition.
• Blood can escape from blood vessels as a result of 3 basic
patterns of injury:
• Intravascular changes: changes of the blood within vessels (e.g.,
↓ clotting factors)
• Intramural changes: changes arising within the walls of blood vessels
(e.g., aneurysms)
• Extravascular changes: changes arising outside blood vessels
(e.g., infection)
• Certain medical conditions can also make patients susceptible
to bleeding.
• These are conditions that affect the normal "hemostatic" functions
of the body.
• Hemostasis involves several components.
• The main components of the hemostatic system include platelets
and the coagulation system.
Basic Mechanisms of Hemostasis
1. Vascular phase.
2. Platelet phase.
3. Coagulation phase.
4. Fibrinolytic phase (rate limiting
step).
1. Vascular Phase
• After tissue injury → immediate vasocontraction occurs.
• Serotonin, histamine, PGs, etc.. cause vasocontraction of the
microvascular bed.
2. Platelet Phase
• Circulating blood platelets are
activated → Aggregate to form
primary vascular plug (decreases
blood loss from small blood vessels
and capillaries) → Adhere to
exposed basement membrane
 Note: Primary hemostasis in detail
• Primary hemostasis results from interactions between platelets, vessel wall, and adhesive
proteins leading to the formation of initial "platelet plug."
• Intact vascular endothelium does not allow adherence of platelets under normal circumstances.
Subsequent to the vascular injury, platelets adhere to collagen and vWF in the sub-endothelial
tissue and undergo a morphological change by assuming irregular surface.
• In the first phase of platelet adhesion, vWF acts as a bridge between endothelial collagen and
platelet surface receptors GpIb. The platelet glycoprotein complex I (GP-Ib) is the principal
receptor for vWF.
• In the second phase of platelet secretion, after adhesion, degranulation from both types of
granules takes place. There occurs release of calcium which binds to the phospholipids that
appear secondary to the platelet activation. This provides a surface for assemblage of various
coagulation factors.
• In the third phase of platelet aggregation, thromboxane A2 produced by activated platelets
provide stimulus for further platelet aggregation. Formation of the platelet plug seals off
vascular injury temporarily.
• Thrombin generation catalyzes the con-version of this fibrinogen to fibrin which adds to the
stability of the platelet plug and is now known as secondary hemostasis. Prostacyclin inhibits
platelet, and the bal-ance between TxA2 and prostacyclin leads to localized platelet aggregation
thus preventing extension of the clot thereby maintaining the vessel lumen patency.
Coagulation Phase
3. Coagulation Phase
• Generation of thrombin and fibrin.
• Involves various proteins: fibrinogen (I), prothrombin (II),
factors V, VII, IX, X, XI, XII, and XIII.
• Factors II, VII, IX, and X are vitamin K dependent.
• Involves 3 separate pathways:
• Intrinsic pathway
• Extrinsic pathway
• Common pathway
• Fibrin polymerizes into a gel that stabilizes the platelet plug
(note: The primary platelet plug is very fragile and is stabilized
via the coagulation system and fibrin formation)
 Note: Coagulation cascade in detail
• The coagulation cascade is a series of reactions, which is classically divided into three pathways:
the contact (also known as the intrinsic) pathway, the tissue factor (also known as the extrinsic
pathway), and the common pathway.
• The intrinsic pathway occurs when negatively charged molecule contact causes a cascade of
factors that produce factor X. The extrinsic pathway occurs when tissue damage causes the release
of tissue factor, creating a smaller cascade that produces factor X. The common pathway merges
both pathways as factor X is used to create thrombin from prothrombin.
• The intrinsic pathway (contact activation pathway) occurs during exposure to negatively charged molecules,
such as molecules on bacteria and various types of lipids. It begins with formation of the primary complex on
collagen by high-molecular-weight kininogen (HMWK), prekallikrein, and factor XII (Hageman factor). This
initiates a cascade in which factor XII is activated, which then activates factor XI, which activated factor IX,
which along with factor VIII activates factor X in the common pathway. Factor VIII is activated by thrombin.
• The main role of the extrinsic (tissue factor) pathway is to generate a “thrombin burst,” a process by which
large amounts of thrombin, the final component that cleaves fibrinogen into fibrin, is released instantly. The
extrinsic pathway occurs during tissue damage when damaged cells release tissue factor III. Tissue factor III
acts on tissue factor VII in circulation and feeds into the final step of the common pathway, in which factor X
causes thrombin to be created from prothrombin.
• In the final common pathway, prothrombin is converted to thrombin. When factor X is activated by either the
intrinsic or extrinsic pathways, it activates prothrombin (also called factor II) and converts it into thrombin
using factor V. Thrombin then cleaves fibrinogen into fibrin, which forms the mesh that binds to and
strengthens the platelet plug, finishing coagulation and thus hemostasis. It also activates more factor V,
which later acts as an anticoagulant with inhibitor protein C, and factor XIII, which covalently bonds to
fibrin to strengthen its attachment to the platelets.
4. Fibrinolytic Phase
• Propagatoin of the clot is limited by fibrinolysis.
• Note: it prevents tissue ischemia by the continued presence of fibrin
clots. These clots may also cause embolism if left alone.
• Tissue plasminogen activator (tPA) released from the endothelial
cells converts plasminogen to plasmin.
• Plasmin degrades fibrinogen and fibrin to fibrin degradation
products
(FDPs)
APPROACH
HISTORY
• Age of onset:
• [Early = congenital + more severe (hemophilia]
• [Late = acquired + less severe]
Note: not necessarily always the case
• Sex: Sex-linked disorders.
• Frequency
• Location/type of bleeding:
• Involving the mucus membranes and/or skin = ↓ PLT
• Involving internal organs and joints = clotting factor
• Duration of bleeding
• Medications: anticoagulants, Ibuprofen or aspirin, long-term use of
antibiotics (associated with GIT bleeding and ecchymoses)
• Associated symptoms
• Review of symptoms
• Feeding history: for vitamin K deficiency
Note: More questions in history

• Severity: did it require hospitalization or intervention.

• Did it stop spontaneously or need pressure application
to stop
• Any other sites of bleeding: GIT, GUT, oral cavity,
nasal cavity, etc.
• Family history.
• Drugs: ibuprofen, Aspirin, etc.
• Ask about liver disease, any previous history of
hepatitis
• Consanguine marriage
Note
• Non-steroidal anti-inflammatory drugs such as ibuprofen,
mefenamic acid, etc. and aspirin inhibit platelet function whereas
anticonvulsants, antihistaminics, antituberculous drugs
especially rifampicin are known to cause thrombocytopenia.
• The overall health of the patient also is a clue to the cause of
bleeding. Congenital bleeding disorders and ITP usually occur
in children who are otherwise well.
• Prolonged antibiotics affect flora and vitamin K.

17
Medical History
• liver disease
• renal disease
• malignancies
• poor nutrition (Vit. K or C deficiency)
Liver Disease
• Decreased synthesis of II, VII, IX, X, XI, and
fibrinogen.
• Prolongation of PT, aPTT and Thrombin Time.
• Often complicated by:
• Gastritis
• Esophageal varices
• DIC
 PHYSICAL
EXAMINATION
Physical Examination
• Physical examination offers further clues to the diagnosis
• Is it bleeding? e.g. fixed drug eruption, erythema nodosum,
viral exanthem and mosquito bites can look like bleeding.
• The examination should determine the presence of petechiae,
ecchymoses, hematomas, hemarthroses, or mucous
membrane bleeding.

21
• Patients with defects in platelet/blood vessel wall interaction
usually have mucous membrane bleeding; petechiae on the
skin and mucous membranes.
• Individuals with a clotting factor deficiency such as factor VIII or
factor IX deficiency have symptoms of deep bleeding into
muscles and joints with much more extensive ecchymoses and
hematoma formation.

8/25/2022 approach to pediatrics bleeding disorders

22
• Petechiae are pathognomonic of platelet-related bleeding.
• Swelling of any joint without a history of significant trauma is
definitely abnormal. Similarly, deep tissue and intramuscular
bleeds should prompt the diagnosis of a coagulation factor
deficiency.

23
Does it sound genetic?
•duration of bleeding history
•congenital v. acquired
•family history
• examine pedigree
• determine inheritance
• Look for hepatosplenomegaly.
• Do a rectal exam for evidence of GI bleeding:
• Look for physical signs and symptoms of diseases related to
capillary fragility: Petechiae secondary to coughing,
sneezing, Valsalva maneuver, blood pressure measurement.
• Note: The possibility of physical abuse must be considered in the
evaluation of any child with unusual patterns of bruising or
bleeding.
Clinical Manifestations of Platelet
disorders vs clotting factors deficiency
Clinical feature Platelet defects clotting factors
deficiency
Site of bleeding Skin, mucous Deep in soft tissues
membrane (gingival, (joints, muscles)
nares, GIT, and GUT)
Bleeding after minor Yes Not usually
cuts
Petechiae Present Absent
Ecchymosis Small, superficial Large, palpable
Hemarthrosis, Rare Common
muscle hematomas
Bleeding after Immediate, mild Delayed, severe
surgery
Clinical Manifestations Typically Associated with Specific Hemostatic
Disorders
Clinical Manifestations Hemostatic Disorders
Mucocutaneous bleeding Thrombocytopenias, platelet dysfunction, von Willebrand
disease

Cephalhematomas in newborns, Severe hemophilias A and B, severe deficiencies of factor

hemarthroses, hematuria, and intramuscular, VII, X, or XIII, severe type 3 von Willebrand disease,
intracerebral, and retroperitoneal afibrinogenemia
hemorrhages

Injury-related bleeding and mild Mild and moderate hemophilias A and B, severe factor XI
spontaneous bleeding deficiency, moderate deficiencies of fibrinogen and factors
II, V, VII, or X, combined factors V and VIII deficiency, 2-
antiplasmin deficiency

Bleeding from stump of umbilical cord and Afibrinogenemia, hypofibrinogenemia,

habitual abortions dysfibrinogenemia, factor XIII deficiency

Impaired wound healing Factor XIII deficiency

Facial purpura in newborns Glanzmann thrombasthenia, severe thrombocytopenia

 LABORATORY
INVESTIGATION
S
Tests of Hemostasis:
• Screening tests:
• Complete blood picture: both platelet count and size.
• Note: NOT CBC [Dr. Mouroge]; Platelets aggregate into clumps and are mistakenly counted as white
blood cells. A very small percentage of the red blood cell population can fall within the threshold for
platelets. And large platelets can be mistaken for red blood cells [1]. the platelet count is probably the
most inaccurate of all the routinely measured hematologic parameters
• Bleeding time: Platelet and blood vessel function
• Prothrombin time (PT): Extrinsic pathway (II, V, VII, and X)
• aPTT: Intrinsic pathway (II, V, VIII, IX, X, XI, and XII)
• Thrombin time: Common pathway (fibrinogen)
• Quantitative fibrinogen assay
• D-dimers: for FDP
• Biochemical screen, including LFT and RFT.
• Specific tests:
• Factor assays: hemophilia.
• Tests of thrombosis: TT, FDP,
• Platelet function studies:
• Adhesion, Aggregation, Release tests.
• Bone Marrow study (note: here, bone marrow study is done routinely)
Platelet Count
• Normally is 150,000 – 450,000 per mm3
• If less than 50,000 per mm3 then the following may
occur:
• Hemorrhagic stroke
• Surgical hemorrhage
• Traumatic hemorrhage
Tests of Platelet Function
• Bleeding time (1-6 minutes): modified Ivy’s test.
• Note: normal duration is 3-8 minutes[1]
• PFA-100 CT (platelet function analyzer – 100 closure time), used
in vWD. Is simple to use.
Neither specific nor predictive.
Is restricted to research studies and clinical trials
Uses of PT/INR
• Evaluates extrinsic coagulation system.
• Measures the presence/ absence of factors I, II, V, VII, and
X.
• Measures the effects coumarin anticoagulants (warfarin)
• Reduction of vitamin K dependent factors (I, II, VII, and X)
• Measures the metabolic aspects of protein synthesis in liver.
• Does not measure the reduction of factors VIII and IX.
• Normal: 10-14 seconds
Activated Partial Thromboplastin
Time (aPPT)
• Considered normal if the control aPTT and test aPTT are within
10 seconds of each other.
• Control aPTT = 15-35 seconds
• Note: normal aPTT is 30-40 seconds.
• It’s altered in hemophilias A and B, and with the use of heparin.
Thrombin Time
• Measures the activity of heparin, FDP, and other para proteins
that inhibit conversion of fibrinogen to fibrin.
• Normal = 9 - 13 seconds
Interpretation
• Causes of prolonged PT:
1. Deficiency of Factor VII,X,V,II,I
2. Vitamin K deficiency
3. Liver disease
4. Oral anticoagulants
Interpretation
• Causes of prolonged aPTT:
1. Deficiency of Factor VIII(Haemophilia
A).
2. Deficiency of Factor IX(Haemophilia B).
3. Heparin therapy.
4. Circulating anticoagulants.
5. Liver disease.
Interpretation
• Causes of prolonged TT:
1. Disorders of fibrinogen:
• Afibrinogenaemia
• Hypofibrinogenaemia.
• Dysfibrinogenaemia.
2. Liver disease
3. heparin therapy
Lab Results in Hemophilia, VWD,
and Vitamin K Deficiency
Hemophilia V W Disease Vit K
Deficiency
Bleeding Normal Increased Normal
Time
PT Normal Normal Increased
aPTT Increased + Increased ± Increased
VIII levels Decreased ++ Decreased Normal
vWF levels Normal Decreased Normal
• In hematology – we can’t do without blood test.
• Only Blood test are not enough.
DISORDERS
Classification of Bleeding
Disorders
1. Vessel wall disorders
2. Platelet disorders
3. Coagulation disorders
Classification of coagulopathies
1. Congenital coagulopathies:
•Hemophilia A
•Hemophilia B
•Factor XI deficiency
•Factor XII, X, V, XIII, and I deficiencies
•Von Willebrand’s disease

2. Anticoagulant-related coagulopathies:
•Heparin
•Coumarin
3. Disease-related coagulopathies:
•Liver disease
•Vitamin K deficiency
•DIC
•Fibrinolytic disorders
HEMOPHILIA
HEMOPHILIA
It is the most common severe inherited bleeding
disorder. Incidence is 1/5000 males.
Types:
1. Hemophilia A (classic hemophilia, X-linked, factor
VIII
(antihemophilic factor) deficiency, 85% of the total).
2. Hemophilia B (Christmas disease, X-linked, factor
IX deficiency, 10-15% of the total).
3. Hemophilia C (Rosenthal syndrome, usually mild,
autosomal
recessive, factor XI deficiency, 2% of the total).
Classification of Hemophilia
A
•
Hemophilia A has 3 severity grades, based factor VIII
level:
Factor VIII Severity Bleeding tendency
<1% Severe Spontaneous
joint/muscle bleeds
1-5% Moderate Bleed after trauma
>5-40% Mild Bleed after surgery

Note: Normal ranges for factor VIII levels are 50%

to 150% of normal
 Note: Factor levels

• By convention, 1 unit of factor is defined as the amount of that

factor pre-sent in 1 mL of normal plasma. Thus 100 mL of normal
plasma contains 100 U/dL of each coagulation factor (100%
activity).
• The hemostatic level, the minimal amount required for cessation of
bleeding, for factor VIII is greater than or equal to 30-40 U/dL,
and for FIX is greater than or equal to 25-30 U/dL.
Factor VIII Deficiency (Hemophilia A,
Classic Hemophilia)
• Essentials of Diagnosis and Typical Features:
• Bruising, soft-tissue bleeding, and hemarthrosis.
• Prolonged activated partial thromboplastin time (aPTT).
• Reduced factor VIII activity.
Clinical Findings of Hemophilia
A
• No racial predilection
• Note: Usually a male patient. Females can be affected, but it’s rare.
• Age: Bleeding manifests begin after 6 months. [when infants
start to crawl or walk (and fall over)]
• severe hemophilia A: spontaneous bleeding episodes involving
skin, mucous membranes, joints (leading to crippling arthritis if not
treated), muscles, and viscera.
• Those with moderate hemophilia A typically have
intermediate bleeding manifestations.
• Mild hemophilia A: bleed only at times of trauma or surgery.
• recurrent hemarthroses that incite joint destruction.
• Although bleeding may occur at any area of the body, the hallmark
of hemophilia is " hemathrosis" i.e., bleeding into joints like knee,
elbow, and ankle joints.
• Note: DDX of joint swelling  hemophilia (hemarthrosis),
septic arthritis, juvenile idiopathic arthritis, etc.
• Neither F8 nor F9 crosses the placenta → bleeding may present at
birth.
• Almost 40% of cases present in the neonatal period, particularly
from ICH, bleeding post circumcision, or prolonged oozing
from heel stick and venipuncture sites.
• Note: Bleeding may also manifest following circumcision,
procedures such as tooth extraction, or oozing from the
umbilical cord following birth.
Complications
• Intracranial hemorrhage.
• Hemarthroses begin early in childhood- joint destruction (ie, hemophilic
arthropathy) (note: a crippling joint disease)
• 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 (note: factor VIII inhibitor bypassing activity) (note: +
steroids, rituximab, plasmapheresis)
• Note: diagnosed by aPTT correction test.
• infection with the human immunodeficiency virus (HIV), hepatitis
B virus (HBV), and hepatitis C virus (HCV). (note: transfusion-transmitted
infections are a serious complication in patients with hemophilia; patients on
cryoprecipitate, FFP, or plasma-based factors are also at increased risk. Those on
recombinant factor VIII or IX, from the start of therapy, are safe [1])
• Immunization with hepatitis is recommended for all hemophilia patients.
Diagnosis
• Note: Compatible clinical picture
• Note: Complete blood picture (the platelets are normal) and bleeding time is not
prolonged (so platelet function is normal as well)
• Note: PT/INR and TT are normal
• Prolonged PTT (partial thromboblastin time).
• ↓ F8 or F9 levels in the plasma.
• Unless the patient has inhibitors to F8, the mixing of normal plasma with patient's
plasma → correction of prolonged PTT.
• Note – aPTT correction test: Extremely useful for distinguishing between a clotting factor
deficiency as the cause of a prolonged APTT and the circulating anticoagulant (inhibitor) is
the qualitative APTT mixing test (APTT correction test). A repeat APTT test is performed in a
mixture of equal volume (1:1) patient plasma and normal plasma. Normalization or
significant shortening of APTT in mixing studies as compared to the patient’s baseline APTT
is indicative of clotting factor deficiency. If the mixture fails to correct the APTT this is
suggestive of the presence of circulating coagulation factor inhibitor
Hemarthrosis
Muscle bleed
Clinical Severity
Treatment of the bleeding episodes

1. Replacement therapy
• Hemarthrosis → F8 20-40 U/kg/dose, repeat the dose daily until the joint
function is normal or back to baseline and consider "additional therapy"
every other day for 7-10 days.
• More severe hemorrhage or surgery → the above dose may be
elevated (50-75 U/kg) or prolonged therapy (1-2 wk) according to the
condition.
• Others → as "cryoprecipitate" which contains 125 U of F8/25 ml / bag,
blood, or plasma (less effective).
Note: 30-40% of FVIII is the minimum acquired to stabilize hemostasis
[Dr. Mouroge]. In conditions such as major surgery[1], severe bleeding[1],
injury very vascular area [Dr. Mouroge], 100% is required.
2. Drug therapy:
• Desmopressin as intranasal spray or oral form (useful in
mild
hemophilia A, not effective for hemophilia B)
• Note: The drug increases endogenous FVIII plasma
concentrations by an average of three- to five-fold by
inducing the release of von Willebrand factor (VWF), the
carrier protein of FVIII and the direct release of FVIII from
Weibel-Palade bodies in endothelial cells[1]
• Aminocaproic acid.
• Note: tranexamic acid (cyclokapron)
Protective measures

1. Prophylactic treatment with FVIII concentrate has been

recommended for many young children with severe hemophilia
to prevent spontaneous bleeding and early joint deformities.
FVIII is given as 20-40 U/kg every other day for variable
periods to achieve trough level of ≥ 1%).
2. Prevention of trauma.
3. Avoidance of aspirin and other NSAIDs.
4. Hepatitis B immunization.
5. Periodic investigations (for patients using plasma derivatives)
like viral hepatitis B & C, AIDS & liver function tests.
6. Genetic counseling
VON WILLEBRAND
DISEASE
VON WILLEBRAND DISEASE
(VWD)
• It is the most common hereditary bleeding disorder.
• Incidence → 1-2% of the population (males = females).
• Functions of VW factor (VWF):
1. Carrier protein for F8.
2. Causes platelets adhesion to the damaged epithelium (note: It
acts as a bridging molecule for normal platelet adhesion
(platelet-subendothelial tissue) and aggregation (platelet-
platelet) at sites of vascular injury under high shear conditions)
• Severe deficiency of VWF may lead to secondary deficiency of
F8.
Clinical presentations

• The bleeding is mild in most cases and restricted to the

mucocutaneous bleeding, easy bruising, epistaxis,
menorrhagia, post-surgical, and post-traumatic bleeding.
• Homozygous VWD (type 3) may → severe bleeding which may
be
clinically similar to, but milder than hemophilia.
Types of VWD
• There are several variants of VWD. The most common variants
are :
1. Type 1: (about 85% of cases). It is caused by the
"quantitative" ↓ of VWF. It is inherited as
autosomal dominant inheritance.
2. Type 2 (4 variants: A,B,M,N): It is rare , more severe, and
less responsive to treatment than type 1. It is caused by the
"qualitatively" abnormal VWF. It is inherited as autosomal
recessive inheritance.
3. Type 3: it is also rare, more severe, and less responsive to
treatment than type 1. It is caused by the absence of VWF. It
is inherited as autosomal recessive inheritance.
4. Platelet-type (pseudo-) VWD: associated
with thrombocytopenia.
Diagnosis

1. Prolonged bleeding time (BT) (note: platelet

dysfunction, but the platelet count is normal[1])
2. Prolonged PTT.
3. Note → Both PTT and BT may be normal in type 1 VWD.
4. VWF assay → ↓ VWF antigen (quantity) or ↓ VWF
activity.
5. There may be ↓ F8 or thrombocytopenia.
Note

• Look for hepatosplenomegaly

• The possibility of physical abuse must be considered in the
evaluation of any child with unusual patterns of bruising or
bleeding.
Complications :
• Complications of bleeding due to VWD are rare.
• In adolescent females, blood loss due to menorrhagia can lead
to severe anemia, either acutely, with signs and symptoms of
hypovolemia, or chronically, caused by iron deficiency.
• Individuals with type 3 VWD can manifest joint or muscle
bleeding similar to individuals with hemophilia.
Treatmen
t
1. Desmopressin (DDAVP) (for type 1 and some of
type 2): A dose 0.3 μg/kg IV will increase the level
of VWF and factor VIII by 3- to 5-fold. Intranasal
DDAVP (Stimate).
2. Note: Antifibrinolytic agents, e.g., tranexamic acid
[cyclokapron], Ԑ- aminocaproic acid
3. Replacement therapy → VWF concentrate (for all
types) (note: often not available here)
• Note: cryoprecipitate and FFP can also be used for
replacement (they do, however, carry a risk of
transmission of infection)
 Hemophilia A Hemophilia B Von
Willebrand
Disease
Inheritance X linked X linked Autosomal dominant

Factor deficiency VIII IV VWF

Bleeding site(s) Muscle,joint Muscle ,joint Mucous

Surgical Skin

Prothrombin time Normal Normal Normal

Activated PTT Prolonged Prolonged Prolonged

Bleeding time Normal Normal Prolonged or normal

Factor VIII Low Normal Normal

VW Normal Normal Low
Factor IX Normal Low Normal
Vitamin k deficiency
•3 main types of vitamin K are :
•K-1, phylloquinone, derived from plants.
•K-2, menaquinone, produced by the intestinal flora.
•K-3, menadione which is a synthetic, water-soluble form used
for
treatment.
•Required for synthesis of Plasma factor II, VII, IX, and
X.
•Hemorrhagic disease in infant that breastfeed
exclusively.
•Give parenteral vitamin K (0.5 to 1 mg) to all
newborns shortly after birth.
Note: Mechanism of vitamin K
deficiency in neonates
• Because of their sterile intestines (has not begun producing
vitamin K) and the minimal concentration of vitamin K in human
milk, newborns are constitutionally vitamin K deficient.
• Breastfeeding prolongs the deficiency, because passively acquired
maternal antibodies delay the establishment of gut flora.
• The maternal vaginal microbiome is an important source for infant
gut microbiome development. However, infants delivered by
Cesarean section (CS) do not contact the maternal vaginal
microbiome and this delivery method may perturb the early
establishment and development of the gut microbiome.
• Newborn vitamin K deficiency is also associated with low
maternal dietary intake of vitamin K during pregnancy
Acquired bleeding
disorder
Usually secondary to underlying disease or drug treatment:
1. Decreased production: e.g. liver disease, Vitamin K deficiency
– neonates, malabsorption
2. Increased consumption: DIC
3. Circulating inhibitors: e.g. antibodies –especially to F. VIII
and associated with SLE.
4. Drugs: heparin and warfarin.
5. Dilution: massive, rapid blood transfusion.
 VASCULAR-
NONHEMATOLOG
I
C DISORDERS
Vascular-Nonhematological
• Child abuse
• Other trauma
• Vasculitis
• Ulcer
• Varices
• Ehler- Danlos syndrome
• Telangiectasia
• Angiodysplasia
Henoch–Schönlein purpura (HSP)
•Known as IgA vasculitis, anaphylactoid purpura, is a disease of
the skin, mucous membranes, and sometimes other organs
commonly affects children. causes palpable purpura (small
hemorrhages) (note: symmetrically distributed over the
extensor surfaces of the limbs and buttocks) often with joint
pain and abdominal pain. With kidney involvement,
(hematuria and proteinuria), but this usually goes unnoticed; in a
small proportion of cases, the kidney involvement proceeds to
chronic kidney disease. HSP is often preceded by an infection,
such as a throat infection.

• Note: + headache, CNS bleeding, testicular pain (extra: neurological

manifestations of HSP, due to hypertension or CNS vasculitis, may also occur.
They include intracerebral hemorrhage, seizures, headaches, and behavior
changes. Other, less common potential manifestations of HSP are orchitis,
carditis, inflammatory eye disease, testicular torsion, and pulmonary
hemorrhage[1])
Note: the DDx of HSP

• The skin disease is typically the first manifestation[1].

• The diagnosis of HSP is a clinical one, and is often straightforward
when the typical rash is present. However, in at least 25% of cases,
the rash appears after other manifestations, making early diagnosis
challenging[1].
• The differential diagnosis for HSP depends on specific organ
involvement but usually includes other small vessel vasculitides,
infections, coagulopathies, and other acute intraabdominal
processes.
• It is not uncommon for patients with HSP presenting with an acute
abdomen to undergo an unnecessary laparotomy (petechiae may be
seen on the omentum??)
• HSP is a systemic vasculitis (inflammation of blood vessels) and
is characterized by deposition of immune complexes containing
the antibody immunoglobulin A (IgA); the exact cause for this
phenomenon is unknown.
Kidney Involvement in HSP
40% of patients develop kidney involvement, almost all have
evidence (visible or on urinalysis) of blood in the urine). only 1%
of all HSP patients develop chronic kidney disease. Hypertension
(high blood pressure) may occur.
Diagnosis
• HSP is a small-vessel vasculitis in which complexes of
immunoglobulin A (IgA) and complement component 3 (C3)
are deposited on arterioles and capillaries.
• The diagnosis is based on the combination of the symptoms,
Blood tests may show elevated creatinine and urea levels (in
kidney involvement), raised IgA levels (in about 50%), and raised
C- reactive protein (CRP) or erythrocyte sedimentation rate
(ESR) results; none are specific for HSP.
• The platelet count is the most important test. HSP is
characterized by nonthrombocytopenic purpura with a normal or
high platelet count and so, distinguishes it from diseases where
low platelets are the cause of the purpura, such as idiopathic
thrombocytopenic purpura, thrombotic thrombocytopenic
purpura, SLE, and leukemia.
• On the basis of symptoms: palpable purpura, abdominal angina,
digestive tract hemorrhage (not due to intussusception),
hematuria. biopsy of the skin may be performed to distinguish the
purpura . immunofluorescence demonstrates IgA and C3.
• Biopsy of the kidney may be performed both to establish the
diagnosis.
• If there is doubt about the cause of the skin lesions, a biopsy of the
skin may be performed to distinguish the purpura from other
diseases that cause it, immunofluorescence demonstrates IgA
and C3 (a protein of the complement system).
• Testing the stool for blood may identify evidence of gut
ischemia. And any question of gut perforation requires
radiological investigation.
Treatmen
t•
Treatment is supportive.
• Analgesics may be needed for the abdominal and joint pains.
• Steroids are generally avoided. [then why list every fucking steroid
without elaboration????]
• Various treatments may be used, ranging from oral steroids to a
combination of intravenous methylprednisolone (steroid),
cyclophosphamide and dipyridamole followed by prednisone.
Other regimens include steroids/azathioprine, and
steroids/cyclophosphamide . Intravenous immunoglobulin (IVIG) is
occasionally used.
• Nelson: systemic steroids are reserved for children with GI
disease and provides significant relief of abdominal pain.
Ehlers-Danlos Syndrome
Note: Collagen disorders typically don’t present in children, and
present in adulthood [?? Dr. Mouroge]
• Congenital disorder of defect in collagen synthesis.
• Patient’s skin lacks its normal resistance to traction and can be
easily pulled away from underlying structures.
• This condition places blood vessels at great risk for disruption even
with minor trauma.
PLATELET
DISORDERS
Platelets:
• Bone marrow - Megakaryocytes
• Life span: 7-10 days
• Normal count: 150-400x109/L
• 36 hours in spleen: about 1/3 of platelets are in the spleen.
• Functions:
• Hemostatic plug formation
• Coagulation factors - release, synthesis
• Surface binding sites for fibrinogen, VWF
• Surface platelet antigens, HPA1
Platelet Disorders
• Thrombocytopenia: quantity of platelets may be reduced by:
• Decreased production in the bone marrow.
• Increased sequestration in the spleen.
• Accelerated destruction
• Treatment: platelet transfusion
• Thrombocytopathies: Qualitative defects in platelet adhesion,
aggregation, or granule release.
Congenital Platelet Disorders

Thrombocytopenic Nonthrombocytopenic

• May-Hegglin anomaly • Glanzman’s thrombasthenia

• Wiskott-Aldricch syndrome • Platelet type von-Willebrand’s
• Neonatal alloimmune disease
thrombocytopenia • Bernard-Soulier syndrome
Acquired Platelet Disorders

Thrombocytopenic Nonthrombocytopenic

• TTP (thrombotic thrombocytopenic • Drug induced

purpura) • Uremia
• Cytotoxic chemotherapy
• Alcohol dependency
• Drug induced
• Liver disease
• Leukemia
• Myeloma
• Aplastic anemia
• Macroglobulinemia
• SLE
• Acquired platelet type von-
• DIC Willebrand’s disease
• Associated with: HIV,
mononucleosis, malaria.
 IDIOPATHIC
(AUTOIMMUNE)
THROMBOCYTOPENI
C
PURPURA (ITP)
Idiopathic (Autoimmune)
Thrombocytopenic Purpura (ITP)
• The most common cause of acute onset of thrombocytopenia
in an otherwise well child.
• Estimated about 1 in 20,000 children.
• A recent history of viral illness is described in 50-65% of cases
of childhood ITP.
• 1-4 weeks after exposure to a common viral infection.
• The peak age is 1-4 years.
• ITP seems to occur more often in late winter and spring after
the peak season of viral respiratory illness.
Pathophysiology

• An autoantibody directed against the platelet surface

develops with resultant sudden onset of thrombocytopenia.
• After binding of the antibody to the platelet surface, circulating
antibody-coated platelets are recognized by the Fc receptor
on splenic macrophages, ingested, and destroyed.
Clinical Manifestations
• The classic presentation of ITP is a previously healthy 1-4 yr
old child who has sudden onset of generalized petechiae and
purpura.
• Often there is bleeding from the gums and mucous membranes,
particularly with profound thrombocytopenia (platelet count <10
× 109/L).
• There is a history of a preceding viral infection 1-4 weeks before
the onset of thrombocytopenia.
• Findings on physical examination are normal, other than the finding
of petechiae and purpura.
• The presence of abnormal findings such as hepatosplenomegaly,
bone or joint pain, or remarkable lymphadenopathy suggests
other diagnoses
Oral petechiae (on the lower lip)
 Classification system
• Depending on the basis of symptoms and signs, but not platelet count;
ITP
is classified as:
• Class 1: No symptoms
• Class 2: Mild symptoms:
• Bruising and petechiae.
• Occasional minor epistaxis.
• Very little interference with daily living.
• Class 3: Moderate symptoms:
• More severe skin and mucosal lesions.
• More troublesome epistaxis and menorrhagia.
• Class 4: Severe:
• Bleeding episodes—menorrhagia, epistaxis, melena—requiring transfusion
or hospitalization.
• Symptoms interfering seriously with the quality of life.
Prognosis
• Severe bleeding is rare (<3% of cases)
• In 70-80% of children who present with acute ITP, spontaneous
resolution occurs within 6 months.
• Fewer than 1% of patients develop an intracranial hemorrhage (note:
this is the most serious complication, but is thankfully not common)
• Note: The child should sleep at a low elevation and should avoid
aggressive play [?? Dr. Mouroge]
• Approximately 20% of children who present with acute ITP go on to
have chronic ITP.
• The outcome/prognosis may be related more to age, as:
• ITP in younger children is more likely to resolve
• The development of chronic ITP in adolescents approaches 50%.
Laboratory Findings
• Severe thrombocytopenia (platelet count <20 × 109/L) is
common, and platelet size is normal or increased, reflective of
increased platelet turnover.
• In acute ITP, the hemoglobin value, white blood cell (WBC) count,
and differential count should be normal.
• Bone marrow examination shows normal granulocytic and
erythrocytic series, with characteristically normal or
increased numbers of megakaryocytes.
Laboratory Findings
• Indications for bone marrow aspiration/biopsy include:
• An abnormal WBC count or differential
• Unexplained anemia
• Findings on history and physical examination suggestive of a bone
marrow failure syndrome or malignancy
• Other laboratory tests should be performed as indicated by
the history and physical examination.
Laboratory Findings

• A direct antiglobulin test (Coombs) should be done:

• If there is unexplained anemia to rule out Evans syndrome (autoimmune
hemolytic anemia and thrombocytopenia)
• Before instituting therapy with IV anti-D.
Diagnosis/
Differential Diagnosis
• Autoimmune thrombocytopenia may be an initial manifestation
of :
• SLE
• HIV infection
• Common variable immunodeficiency
• Lymphoma (rarely)
Treatmen
t
• Platelet transfusion in ITP is usually contraindicated unless
life- threatening bleeding is present (note: e.g., intracranial
hemorrhage, such as a child presenting with headache and
vomiting) (Antiplatelet antibodies bind to transfused platelets
as well as they do to autologous platelets) (note: The transfusion
may also induce further production of antibodies??)
Treatmen
t•
Initial approaches to the management of ITP include the following:
• No therapy other than education and counseling of the family and
patient for patients with minimal, mild, and moderate symptoms, as
defined earlier.
• This approach is:
• Far less costly
• Side effects are minimal
Treatmen
t•
Intravenous immunoglobulin (IVIG)
• IVIG at a dose of 0.8- 1.0 g/kg/day for 1-2 days induces a rapid rise
in platelet count (usually >20 × 109/L) in 95% of patients within 48 hr.
• IVIG appears to induce a response by downregulating Fc-mediated
phagocytosis of antibody-coated platelets.
• IVIG therapy is :
• Expensive.
• Time-consuming to administer.
• After infusion, there is a high frequency of headaches and vomiting, suggestive
of IVIG-induced aseptic meningitis.
Treatmen
t•
Intravenous anti-D therapy:
• For Rh positive patients IV anti-D at a dose of 50-75 μg/kg causes a rise
in platelet count to >20×109/L in 80-90% of patients within 48-72 hours.
Treatmen
t•
Prednisone:
• Note: Anti-D and IVIG are expensive so steroids are often used here.
• Doses of prednisone of 1-4 mg/kg/24 hr.
• Note – Dr. Mouroge: 4 mg/kg for 5 days or smaller dose longer
duration (2 mg/kg for 21 days); follow platelet counts.
• Corticosteroid therapy is usually continued for 2-3 weeks or until a
rise in platelet count to >20 × 109/L has been achieved, with a rapid
taper.
• long-term side effects of corticosteroid therapy:
• Growth failure
• Diabetes mellitus
• Osteoporosis
•Note – novel therapy: Newer treatments, such as the thrombopoietin receptor
agonists, have transformed ITP care. Eltrombopag, given oral; Romiplostim given SC.
It stimulates bone marrow production of platelets. It’s used in refractory cases [1].
Intracranial hemorrhage
• If ICH occurs multiple modalities should be used,
including:
• Platelet transfusion
• IVIG
• High-dose corticosteroids
• Prompt consultation by neurosurgery and surgery.
Splenectomy in ITP
• The role of splenectomy in ITP should be reserved for 1 of
2 circumstances:
1. The older child (≥4 yr) with severe ITP that has lasted >1 yr
(chronic ITP) whose symptoms are not easily controlled with
therapy
2. Life-threatening hemorrhage (intracranial hemorrhage) complicates
acute ITP, if platelet count cannot be corrected rapidly with transfusion
of platelets and administration of IVIG and corticosteroids
Note: now less commonly used.
summary
1. Immune mechanisms:
A. Primary —immune thrombocytopenia (ITP)
B. Secondary—SLE, lymphoma
C. Drugs—Thiazides, Sulfonamides
2. Excessive consumption:
A. Disseminated intravascular coagulation (DIC)
B. Sequestration with splenomegaly
Qualitative Disorders of Platelet
Funciton
• Inherited: e.g., Bernard Soulier syndrome, thrombasthenia
• Acquired: e.g., myeloproliferative diseases, uraemia.
• Drugs, e.g., aspirin and non-steroidal anti-inflammatory
drugs.
Indications of bone marrow
examination
1. Abnormal WBC count or differential count.
2. Unexplained anemia.
3. Suggestion of bone marrow disorders by history &
physical
examination.
4. Lymphadenopthy and/or organomegaly.
Differential diagnosis
• Exposure to medications
• Splenic sequestration due to previous Portal hypertension
• Early aplastic process as fanconi anemia
• Amegakaryocytic thrombocytopenia • HUS • DIC • SLE
• Throbocytopenia & absent radius (TAR) • HIV • Lymphoma
• Wiskot-Aldrich syndrome
 Note: clinical scenarios and notes
• 2 cases, one in which the child was previously healthy and the mother noticed
multiple red spots on the back, and the second in which the lower limb had bluish
discoloration. The first one has ITP; bleeding on such sites should be taken seriously.
The second case doesn’t have anything significant and is simply due to trauma from
rough playing when it’s present on the lower limbs.
• Newborn, develops reluctance to feed, and looks very pale, and consciousness
deteriorates.
• Is the child feverish? No, he was well.
• History of labor: Mode of delivery? Any complications?
• Jaundice? No.
• Any bleeding? Check for CNS (Intracranial) bleeding; check the fontanelle, which would
be tense. This can be confirmed by US or MRI. The cause could be vitamin K deficiency
(PT and PTT are prolonged), hemophilia, etc. Factor VII deficiency has a particular
tendency to cause CNS bleeding in neonates [Dr. Mouroge]
• Child admitted for treatment of severe pneumonia. He developed diarrhea with a
streak of blood. Heavy use of antibiotics can cause bleeding due to disrupting of
normal flora and reduce vitamin K levels. The bleeding defect is usually corrected
within few hours after parenteral administration of vitamin K.
THANK YOU
Case Study
• 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?
Scenario #1
• PT-Normal
• PTT-Normal
• TT-Normal
• Fibrinogen -Normal
• Platelet count-Normal
Interpretation
• Primary hemostasis disorder.
• Disorders of platelet function (cong or acquired).
• Vascular disorders of hemostasis.
• Factor XIII deficiency( fibrin stablizing factor)
• vWD.
Scenario # 2
• PT-Eleveted
• PTT-Normal
• TT-Normal
• Fibrinogen -Normal
• Platelet count-Normal
Interpretation
• Factor VII deficiency.
• Liver disease.
• Vit K deficiency.
• At the start of oral anticoagulant therapy.
• Mild deficiency of Factor II, V, X.
 Scenario # 3
• PT-Normal
• PTT-Eleveted
• TT-Normal
• Fibrinogen -Normal
• Platelet count-Normal
Interpretation
• Congenital deficiency of F VIII, FIX,.
• vWD
• Heparin
• Circulating anticoagulants-Specific (Anti factor VIII).
• Second line investigations
• Mixing test.
• Factor VIII & factor ix assay
 Scenario # 4
• PT-Eleveted
• PTT-Eleveted
• TT-Normal
• Fibrinogen -Normal
• Platelet count-Normal
Interpretation
• Vit k def.
• On oral anticoagulants.
• Liver dis.
• Rare congenital or acq. Deficiency of factor V, X,
II
• Combined factor V+VIII deficiency.
2nd line investigations
• Mixing test.
• Specific factor assay.
• Liver function test.
Tests are normal-Now what?
• simple purpura
• senile purpura
• Factor XIII deficiency
• alpha-2-antiplasmin deficiency
• mild factor deficiency
• amyloidosis
• vascular disorders
Still more?
• Hereditary hemorrhagic telangiectasia
• scurvy
• Ehlers-Danlos syndrome
• Henoch-Schonlein purpura
• the un-diagnosable fibrinolytic defect
Answer: True
Coagulation phase INVOLVES VARIOUS PROTEINS: Fibrinogen, prothrombin, FS-V,VII,IX,X,XI,XII & XIII.
Vitamin K dependent-FS-II,VII, IX & X.
• True
• False
Fibrinogen
Coagulation phase may include
Ali had to have tooth extraction which was followed by
extensive blood loss from the site of the tooth, the most likely
problem is:
A. He had been on painkiller
B. He may have coagulation defect
C. He was malnourished child
D. Bad oral hi gen with vit. C deficiency
E. His platelets count is 100.000

Answer: B
How do you treat ITP as first line?
A. Chemotherapy drugs
B. Steroid therapy
C. Steroid and IVIG
D. Platelet infusion
E. Splenectomy

Steroid is a cheap drug, taken orally with a good response

Answer: B