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Bleeding disorder
 Dr M A Maleque Molla, FRCP, FRCPCH
September 14 2015
OBJECTIVES
 Overview of hemostasis
 Clinical approach in making a diagnosis
 Review the most common bleeding conditions
 Discuss the current treatment strategies
Hemostasis
 Hemostasis is the active process that clots blood in
areas of blood vessel injury & simultaneously limits
the clot size only to the areas of injury.
 Over time, the clot is lysed by the fibrinolytic system
 Normal hemostasis needed to;
 Arrests bleeding
 Keeps blood in fluid state
 Repair and reestablish the blood flow through the
injured vessels
 Remove hemostatic plug and normal blood flow is
restored
Hemostasis(cont.)
Normal hemostasis requires integrity of 3 elements:
1. Blood vessels
2. Platelets
3. Soluble clotting factors
Hemostasis(cont.)
Role of Blood vessels
 Injury to the blood vessels
elicit 3 response to control
the bleeding;
1. Vasoconstriction
2. Activation of platelets and
coagulation factors
3. Release tissue factor which
activates extrinsic
coagulation path way
Hemostasis(cont.)
Role of Platelets
Platelets involves in hemostasis
by;
 Platelet adhesion
 Platelet aggregation
 Platelet secretion:
 Serotonin, Thromboxane A2
-Augment vasoconstriction
 ADP- Platelet aggregation
Hemostasis(cont.)
Role Clotting factors
Clotting factors involves in
hemostasis by;
 Initiating process of
coagulation via series of
reaction
 Extrinsic path way
 Intrinsic path way
 Common path way
Coagulation factors
 Plasma coagulation factors are protein synthesize in liver &
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
endothelium of blood vessels.
II, VII, IX, X are called vitamin K dependent clotting
factors.
Factors have specific name but are known by Roman
numeral from I-XIII.
There are 12 factors.
Factors remains inactive form & indicated by simple
numerals, except factors III & IV.
A lower case “a” indicates the active factor e.g. factor IXa
Coagulation Factors
 Factor I (Fibrinogen): Precursor of fibrin, which forms clot
 Factor II (Prothrombin).
 Factor IIa (Thrombin): most important protease of the coagulation
pathway
 Factor III (Tissue thromboplastin): lipoprotein complex from tissues.
 Factor IV: Ionized calcium .
 Factor V (Proaccelerin); Essential to the thromboplastin formation
 Factor VII (proconvertin); Activates tissue thromboplastin and the
acceleration of the production of thrombin from prothrombin
 Factor VIII (Antihemophilic Factor): Consists von Willebrand factor (vWF)
 Factor IX (Plasma Thromboplastin component); It is an essential
component of the intrinsic thromboplastin generating system
 Factor X (Stuart Factor)
 Factor XI (Plasma Thromboplastin Antecedent); Essential to the intrinsic
thromboplastin-generating mechanism
 Factor XII (Hageman factor)
 Factor XIII (Fibrin-Stabilizing Factor).
Intrinsic pathway
Extrinsic Pathway
HMK, PK
Ca ++
XIIa
XII
Ca ++
XI
XIa
VII
PL
Ca ++
IX
X
Tissue factor (TF)
Ca ++
IXa VIIa
VII
XIII
Xa
Pl,Va,Ca++
Common Pathway
II (Prothrombin) IIa (Thrombin)
PL=Platelet, phospholipid
Fibrinogen Fibrin (Soft clot)
XIIIa
Fibrin Polymer (Hard clot)
Fig. Coagulation cascade
Intrinsic pathway
Intrinsic pathway
 Intrinsic pathway begins with
formation of the primary complex on
collagen by
 High-molecular-weigh kininogen
(HMWK),
 Prekallikrein(PK),
 FXII (Hageman factor).
 Prekallikrein is converted to kallikrein
and activate FXII to FXIIa.
 FXIIa converts FXI into FXIa.
 Factor XIa activates FIX to IXa,
 FIXa + with co-factor FVIIIa form the
tenase complex, which activates FX to
FXa.
HMK, PK
Ca ++
XIIa
XII
XI
Ca ++
IX
XIa
VII
PL
Ca ++
X
IXa
Xa
Extrinsic pathway
 Following
damage to the
blood vessel, FVII leaves the
circulation
 FVII comes into contact with
tissue factor (TF) & forms
an activated complex (TFFVIIa).
 TF-FVIIa activates F X to Xa.
Extrinsic Pathway
Tissue factor (TF)
VIIa + TF
X
Xa
VII
Common pathway
 FXa and its co-factor FVa
form the prothrombinase
complex, which activates
prothrombin to thrombin.
 Thrombin then activates
fibrinogen to fibrin
 Finally leads to formation of
fibrin network.
Final common Pathway
Xa +Va
II (Prothrombin)
IIa (Thrombin)
Fibrinogen
Fibrin
Mechanism of Hemostasis
Injury to a blood vessel
Immediate response
blood vessel constrict
Platelets adhere and aggregate at the site of the injury
and form a plug
Activated platelets secretes & initiate the coagulation
factors forming a fibrin network or clot completely.
WBC, RBC & platelets are trapped and form a solid
plug of blood(coagulation)
seals off the injury
vessel completely.
Finally slow lysis of the clot, fibrinolysis, begins and
the site of the injury is repaired.
Phase I.
Primary
hemostasis
3 to 5 min
Phase II
Coagulation
5 to 10 min
Phase III.
Fibrinolysis
48-72 hour
Bleeding disorder
 Bleeding disorders are coagulopathies with
reduced clotting of the blood
 Can be congenital or aquired.
Bleeding disorders
 Bleeding for longer than normal is due to
defect in hemostasis
 Can be due to the abnormality of
1.
2.
3.
Blood vessels
Platelet
Clotting factors leading to coagulation
abnormality
1. Disorders of blood vessels
 Excessive capillary fragility -Ehlers-Danlos
syndrome
 Vasculitis e.g. Henoch-Schonlein purpura
 Hereditary hemorrhagic telangiectasia
 Vitamin C deficiency
2. Disorders of Platelets
 Normal platelet 150,000-350,000 x 103/µl
 Thrombocytopenia(<150,000 x 103/µl) is the most common
cause of bleeding.
 Platelet disorder may be
1.
Quantitative disorder- Decrease number of platelet;
 Decrease production





Increase destruction



2.
Bonemarrow failure e.g pancytopenia
Congnital Amegakaryocytic thrombocytopenia
Thrombocytopenia absent radius syndrome(TAR) AR
Wiskott-Aldrich syndrome, XR
Immune mediated thrombocytopenia(ITP)
Hypersplenism
Dessiminated intravascular coagulation(DIC)
Qualilative disorder-Abnormal platelet function;
 Congenital e.g Glanzmann’s disease. Bernard-Soulier synd
 Aquired e.g Drug induced like Aspirin
3. Disorders of Coagulation factors
 Congenital deficiency- usually single factor
defect;
 Hemophilia A, B, C
 von Willebrand’s disease
 Acquired-usually multiple factor deficiency;
 Disseminated Intravascular coagulation(DIC):
Consumption of platelet, FII, V, VIII
 Vit K Deficicency; Deficiency of Vit k dependent
factors II, V, VII, IX & X
 Liver disease.
Disorders of Coagulation factors(cont..)
 Deficiencies of most procoagulant proteins lead to
bleeding
 Deficiencies of contact factors e.g. prekallikrein, high
molecular weight kininogen, and Hageman factor
[XII] are not associated with a predisposition to
bleeding
Bleeding disorder
Presentation
 Bruising may be spontaneous or recurrent:
 Large bruises on the trunk are more indicative of a bleeding
disorder.
 Prolonged bleeding:
 After minor cuts or abrasions.
 After circumcision in young infant.
 Nosebleeds lasting >10 minutes despite compression
(especially in children).
 Bleeding from gums without gingival disease.
 Following dental extraction.
 Severe menorrhagia causing anemia, with normal uterus.
 Postpartum hemorrhage in adult.
 After injections or surgical procedures.
Bleeding disorder (cont..)
History
 Family history of bleeding tendency.
 Current medication:
 Aspirin, non-steroidal anti-inflammatory
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drugs, warfarin.
Alcohol intake in adolescelent & adult.
Other constitutional symptoms - eg, malaise,
weight loss.
Past history or thrombosis (can be suggestive of
thrombophilia).
Previous blood transfusions.
Renal or hepatic impairment.
Bleeding disorder (cont..)
Physical
 Skin, palate and gums for:
 Petechia (non-blanching
haemorrhagic spot <2 mm diameter)
 Purpura (2-10 mm diameter)
 Bruising >10 mm diameter
 Ecchymosis (>10 mm diameter)
 Joints for hemarthrosis.
 Fundi for retinal hemorrhages.
 Reticulo- endotheilial system
Comparing coagulation factor and platelet defects
Coagulation
factor defects
Platelet disorders and von
Willebrand's disease
Bruising on trunk and limbs
Large bruises
Small bruises
Bleeding from cuts
Relatively slight
Profuse
Nosebleeds
Uncommon
Common, frequently
profuse and of long duration
Gastrointestinal bleeding
Uncommon
Common
Haematuria
Common
Rare
Haemarthrosis
In severe
haemophilia
Very rare
Bleeding after surgery or dental
extraction
Up to a day's
delay before
bleeding occurs
Immediate bleeding
Karnath B; Easy Bruising and Bleeding in the Adult Patient, 2005
Investigations
 FBC, blood film and platelet count: may detect ITP,
leukaemia, lymphoma or abnormal platelets.
 U&Es: to exclude uremia causing a platelet disorder.
 LFTs: to detect hepatic disorder.
 Bone marrow biopsy.
Investigations(cont..)
 A coagulation screen
 APTT: Measures intrinsic pathway (F I, II, V, VIII, IX, X, XI
and XII deficiency) and the common pathway
 PT: Measures extrinsic and final common pathway of the
coagulation cascade, thus can detect factor I, II, V, VII or X
deficiency
 Thrombin time: Measures the final step in the clotting
cascade.
 Bleeding time : sometimes used in the investigation of vWD
although it has poor specificity
 Fibrinogen: detect afibrinogenaemia or hypofibrinogenaemia
 D- Dimer: Fibrin degradation product. Measure to detect
DIC, Deep vein thromosis.
 INR- The INR is a standardized prothrombin time designed
to account for differences in thromboplastin. Normal range
0.9 - 1.1
Investigations(cont..)
 Specific factor assays:
 F VIII or FIX to determine severity of
hemophilia;
 Factor VIII and vWF in vWD
 Other factor deficiency
 Gene analysis looking for specific gene
defects.
Investigations(cont..)
Tests in bleeding disorders
Platelet
count
PT
Haemophilia A
N
N
N
Factor VIII low
Haemophilia B
N
N
N
Factor IX low
Von
Willebrand's
disease
N
N
Liver disease
Low
DIC
Low
N- Normal,
APTT
B
T
TT
Additional tests
or N
VWF and factor
VIII activity low and
impaired ristocetininduced platelet
aggregation
N
(rarely
)
=Prolonged
Hayward CP; Diagnosis and management of mild bleeding disorders. Hematology Am Soc Hematol Educ Program. 2005:423-
Coagulopathies
 Congenital
 Hemophilia A: Deficiency of FVIII, Inheritance XR
 Hemophilia B: Deficiency of FIX , Inheritance XR
 Hemophilia C: Deficiency of FXI, Inheritance AR
 Deficiency of other coagulation factors : I, II, V, VII, IX, X and XIII
 Deficiency of XII factor, prekallikrein or kininogen, protein C and S
(without excessive bleeding)
 von Willebrand’s disease (angiohemophilia) AD
 Aquired:
 Vit K deficiency; Hemorrhagic disease of the new born, Liver
disease
 DIC
von Willebrand Disease

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The most common inherited bleeding disorder
Inheritance is usually AD, rarely AR.
Occurs in 1% of the population
Less than 10% of patients have bleeding events due
to vWD.
 Caused by deficiency of von Willebrand
Factor(vWF).
 vWF may be either
 Quantitatively deficient -Type 1 or Type 3
 Qualitatively abnormal- type 2.
 80% of patients have classic type 1 disease - a
mild to moderate deficiency of vWF.
Clinical features
 Easy bruise
 Epistaxis or gingival bleeding
 Post-surgical bleeding
 Bleeding post-dental extraction
 Post-partum hemorrhage
 Menorrhagia
In severe disease may have manifestations similar
to hemophilia A (hemarthrosis)
Investigation
 Measurement of:
 vWF -the vWF antigen (vWF:Ag).
 vWF activity (vWF:Act)- is measured functionally
in the ristocetin cofactor assay (vWFR:Co),
which uses the antibiotic ristocetin to induce vWF
to bind to platelets.
Classification of von Willebrand disease
Type
Inheritance
VWF activity
RIPA
AD
Decreased
Decrease
Type 2A
AD or AR
Decreased
Type 2B
AD
Decreased
Increase
Type 2M
AD or AR
Decreased
Decrease
Type 2N
AR
Normal
Normal
Type 3 (severe)
AR
Markedly decreased or
absent
Markedly
Decrease
Type 1 (partial
quantitative deficiency)
Type 2 (qualitative
variant)
RIPA: ristocetin-induced platelet aggregation
Decrease
Treatment
 The treatment depends on the severity of the bleeding.
 The five categories of medications for the treatment of
von Willebrand disease (VWD) include
 Desmopressin (DDAVP);
 Replacement therapy with vWF containing
concentrates(Humate P)
 Antifibrinolytic drugs; Epsilon aminocaproic
acid(EACA) and Tranexamic acid
 Topical therapy with thrombin or fibrin
 Estrogen therapy in some settings in women
Treatment Guidelines in VWD
TYPE
TREATMENT
1
DDAVP
2A
DDAVP/FVIII-vWF
2B
FVIII-vWF
2M
FVIII-vWF
2N
FVIII-vWF
3
FVIII-vWF
DDAPV=1-desamino-8-D-arginine vasopressin
Hemophilia
 Caused by an absence or decreased amount of a
procoagulant.
 VIII -Hemophilia A
 XI -Hemophilia B
 XI –Hemophilia C
 Incidence
 Hemophilia A - 1:5,000
 Hempohilia B – 1: 30, 000
Types of Hemophilia A & B
 Severe: <1% factor activity level - Spontaneous bleeds
 Moderate: 1 to 5% activity -Trauma/surgery bleeds
Occasional joint bleeds
 Mild: 5 to 30% activity - Major trauma/surgery Rare
joint bleeds
 Hemophilia A & B are clinically indistinguishable.
 The hemostatic level for factor VIII is >30-40%, and
for factor IX, it is >25-30%
 The lower limit of levels for factors VIII and IX in
normal individuals is approximately 50%.
Haemophilia A
 Due to the deficiency of factor VIII
 Inharitence XR. Males are affected.
 There is usually a clear family history but sporadic
cases do occur due to novel mutations or effects of
mosaicism
 Females born to affected fathers can (rarely) have
the disease due to homozygosity for the gene,
where there is marriage to close relatives
 Severity of disease depends upon levels of
remaining factor activity
Haemophilia A
Severity of factor VIII deficiency
Severity
Factor VIII
activity level
Age of presentation
Percentage of
sufferers
Severe disease
<1%
Infancy
43-70%
Moderate
disease
1-5%
Before 2 years
15-26%
Mild disease
>5%
Older than 2 years
15-31%
Haemophilia A
Severe disease
 Neonatal bleeding in around a third to a half of cases.
 This may follow circumcision or other operative procedures.
 Neonatal intracranial hemorrhage can be a presenting feature of in
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about 3-4%,
Hematoma and prolonged bleeding from the cord or umbilical area.
Intracranial hemorrhage occurs in about 5% of all untreated cases.
History of spontaneous bleeding into joints, especially the knees,
ankles and elbows, without a history of significant trauma.
Spontaneous hemarthroses are virtually pathognomonic.
Intramuscular haemorrhage may also occur.
Gastrointestinal and mucosal haemorrhage do occur but are more
often associated with hemophilia B/von Willebrand's disease.
Haematuria may be a feature, which can vary from self-limiting minor
episodes to gross haematuria.
Haemophilia A
Mild & Moderate disease
Moderate disease
 Often presents with bleeding following
venepuncture.
 Bleeds after minor trauma or surgery
Mild disease
 Only bleed after major trauma or surgery.
Investigations
 APTT- usually prolonged in Hemophilia A & B, but can
be normal in mild disease.
 Specific factor assay:
 Factor VIII C - is reduced in Hemophilia A
 F IX is reduced in Hemophilia B
 Percentage of factor activity represents severity of
disease
 Prothrombin time, bleeding time, fibrinogen levels
and von Willebrand factor - are normal.
Management
 Early, appropriate factor replacement therapy is the aim of
optimal hemophilia care
 For treatment of acute bleeds, target levels by hemorrhage
severity are as follows:
 Mild hemorrhages (eg, early hemarthrosis, epistaxis, gingival
bleeding): Maintain an FVIII level of 30%
 Major hemorrhages: (eg, hemarthrosis or muscle bleeds with
pain and swelling, prophylaxis after head trauma with negative
findings on examination): Maintain an FVIII level of at least 50%
 Life-threatening bleeding episodes: (ie, major trauma or
surgery, advanced or recurrent hemarthrosis, CNS bleeding):
Maintain an FVIII level of 80-100%
Prophylaxis
 Prophylaxis to be considered for children
with severe hemophilia
 Usually initiated with the first joint
hemorrhage
 For routine prophylaxis, rVFIIIFC is infused
every 4 days, whereas other available
recombinant FVIII products are administered
every 2-3 days.
Disseminated Intravascular
Coagulation(DIC)
 Called Consumptive coagulopathy
 Usually there is a balance between the clotting and lysis
systems. This balance is altered.
 In DIC, the coagulation mechanism is activated
inappropriately and in a diffuse way by tissue damage from
a variety of underlying diseases .
 Coagulation factors, especially platelets, fibrinogen, and
factors II, V, and VIII, are consumed.
 This may lead to thrombosis in the sub acute or chronic
form but more often hemorrhage occurs as the clotting
factors are exhausted.
Risk factors
 Infection e.g septicaemia
 Major trauma including burn
 Malignency
 Some collagen disease
 Incompatible blood transfusion.
 Heat stroke.
 Dissecting aortic aneurysm.
 Some snake bites
Clinical feature
 Obvious features are usually those of the
underlying condition
 There may be large bruises or spontaneous
bleeding at venepuncture sites, on the soft palate,
legs and the site of trauma.
 There may be gastrointestinal or pulmonary
hemorrhage or evidence of peripheral gangrene or
thrombosis suggests the diagnosis of DIC.
Investigation
 PT & aPTT are elevated.
 Platelet counts is typically low, especially in acute




sepsis-associated DIC, but may be increased in
malignancy-associated chronic DIC.
Fibrinogen level low.
The D-dimer elevated.
Elevated fibrin degradation products (FDPs ).
Microangiopathic hemolytic anemia .
Scoring system for overt DIC
 Platelet count:
 >100 x 109/L = 0, <100 x 109/L = 1, <50 x 109/L = 2
 Elevated fibrin marker - eg, D-dimer, fibrin degradation
products –

no increase = 0, moderate increase = 2, strong increase = 3)
 Prolonged PT :
 <3 secs = 0, >3 but <6 secs = 1, >6 secs = 2)
 Fibrinogen level:
 >1 g/L = 0, <1 g/L = 1
 Calculate score:
 ≥5 - compatible with overt DIC: repeat score daily
 <5 - suggestive for non-overt DIC: repeat next 1-2 days
Management
 Treat the underlying cause.
 Support the patient by correcting hypoxia, acidosis, and






poor perfusion.
Platelet transfusion if <50 x 109/L
Fresh frozen plasma
Prothrombin concentrate
Severe hypo fibrinogenemia may need replacement of
fibrinogen or cryoprecipitate
In cases of DIC where thrombosis predominates, e.g.arte
rial or venous thromboembolism, severe purpura
fulminans, therapeutic doses of heparin should be
considered
Severe sepsis and DIC may be treated with recombinant
human activated protein C