Bleeding Disorders

part 2
MBS 400
Learning objectives
To introduce the students to abnormal bleeding
To discuss the different type of Coagulation disorders
To discuss the clinical features
To discuss the laboratory findings in Coagulation
disorders
Introduction
Abnormal bleeding may result from:
1. Vascular disorders
2. Thrombocytopenia
3. Defective platelet function
4. Defective coagulation
Pattern of bleeding is relatively predictable depending
on the aetiology
Vascular & platelet disorders tend to be associated with
bleeding from mucous membranes and into the skin
In coagulation disorders, bleeding is often into joints
or soft tissue
Coagulation disorders
FACTORS
Review of the Normal Coagulation
Cascade (In ViVo)
Review of the Normal Coagulation
Cascade (In Vitro)
Hereditary coagulation disorders
Haemophilia A (factor VIII deficiency)

Haemophilia B (Christmas disease factor IX deficiency

Von Willebrand disease (VWD)

Others are rare

Haemophilia A
Most common of hereditary clotting factor
deficiencies

Prevalence is about 30 – 100 per million population

Inheritance is sex-linked

A third of cases have no family history and result from

mutation
Molecular genetics
Factor VIII gene is situated near the tip of the long
arm of the X-chromosome
Half the patients have missense or frameshift
mutations or deletions in the factor VIII gene
Defect is absence or low level of plasma factor VIII
In others the factor VIII gene is broken by an inversion
at the end of the X-chromosome
This mutation leads to a severe clinical form of
haemophilia A
Inheritance patterns
Clinical features
Infants may develop profuse post-circumcision haemorrhage
or joint & soft tissue bleeds & excessive bruising when they
start to be active
Recurrent painful haemarthroses & muscle haematomas
dominate the clinical course of severely affected patients
If inadequately treated, lead to joint deformity & disability
Prolonged bleeding occurs after dental extractions
Spontaneous haematuria & GIT haemorrhage can occur
Operative & post-traumatic haemorrhage are life-threatening
Spontaneous intracerebral haemorrhage is an important
cause of death
Laboratory findings
The following tests are abnormal
1. aPTT
2. Factor VIII clotting assay
PFA-100, bleeding time and prothrombin time (PT) are normal
Carriers are detected with DNA probes
Chorionic biopsies at 8-10 weeks gestation provide sufficient
foetal DNA for analysis
Foetal blood obtained from the umbilical vein at 16-20 weeks
can be tested for factor VIII levels
However, this method is only used if DNA analysis is
uninformative
Factor IX deficiency (Haemophilia B,
Christmas disease)
Inheritance & clinical features identical to Haemophilia A
Distinguished by specific factor assays
Lower incidence
Synthesis is vitamin K dependent
Carrier detection is performed as for Haemophilia A
Principles of replacement therapy are similar to those for
haemophilia A
Factor IX has a higher biological half-life & is given less
frequently than factor VIII
aPTT & factor IX clotting assays are useful for diagnosis
Other tests are normal
Von Willebrand Disease
Due to reduced level or abnormal function of von
Willebrand factor (vWF)
Genetic basis is a missense or null mutation
VWF is produced in endothelial cells &
megakaryocytes
Has two (2) roles:
1. Promotes platelet adhesion to sub-endothelium at
high shear rates
2. Carrier molecule for factor VIII i.e protects it from
premature destruction
Pathophysiology
Chronic elevation of VWF is part of the acute phase
response to injury, inflammation, neoplasia or
pregnancy
Synthesized as large 600kDa dimeric protein which
forms multimers up to 20x10⁶ Da
Three types of VWD have been described (Types 1,2
&3)
Type 1 accounts for 75% of cases
Type 2 is divided into four subtypes depending on the
functional defect
Classification of vWD
Clinical features
Most common inherited bleeding disorder
Inheritance is autosomal dominant
Women are worse affected than men
Typically mucous membrane bleeding (e.g epistaxes,
menorrhagia), excess bleeding from superficial cuts &
abrasions, and operative & post-traumatic
haemorrhage
Haemarthroses & muscle haematomas are rare, except
in type 3 disease
Laboratory findings
1. The PFA-100 test is abnormal. This has largely replaced the bleeding
time
2. Factor VIII levels are often low. If low, a factor VIII/VWF binding assay
is performed
3. The APTT may be prolonged
4. VWF levels are usually low
5. There is defective platelet aggregation by patient plasma in the
presence of ristocetin (VWF/Rco). Aggregation to other agents (ADP,
thrombin or adrenalin) is usually normal
6. Collagen-binding function (VWF:CB) is usually reduced
7. Multimer analysis is useful for diagnosing different subtypes
8. The platelet count is normal except for type 2B disease (where it is low)
Hereditary disorders of other
coagulation factors
All these disorders (deficiency of fibrinogen,
prothrombin, factors V, VII, combined V & VIII, factors
X, XI, XIII) are rare

In all, the inheritance is autosomal recessive

Bleeding only occurs after trauma such as surgery

Treatment is with fibrinolytic inhibitor, factor

concentrate or fresh frozen plasma
Summary
Acquired coagulation
disorders
Vitamin K Deficiency
Fat soluble vitamin K obtained from green vegetables & bacterial
synthesis in the gut
Deficiency may present in newborns (haemorrhagic disease of
the newborn) or later in life
Causes of deficiency include inadequate diet, malabsorption or
inhibition of vitamin K by drugs i.e warfarin, which act as vitamin
K antagonists
Warfarin is associated with a decrease in functional activity of
factors II, VII, IX, X, protein C & S
Plasma levels remain normal
Warfarin interferes with the action of vitamin K epoxide
reductase leading to a functional vitamin K deficiency
Haemorrhagic disease of the
newborn
Vitamin K-dependent factors are low at birth
Fall further in breast-fed infants in first few days of life
Liver cell immaturity, lack of gut bacterial synthesis &
low quantities in breast milk may all contribute to a
deficiency
Causes haemorrhage usually on second to fourth day
of life, and occasionally during first 2 months
PT & APTT both abnormal
Platelet count & fibrinogen normal with absent fibrin
degradation products
Vitamin K deficiency in children
or adults
Deficiency due to obstructive jaundice, pancreatic or
small bowel disease occasionally causes a bleeding
diathesis in children or adults
Both PTT & aPTT are prolonged
There are low plasma levels of factors II, VII, IX & X
Prophylaxis: vitamin K 5mg/day orally
Active bleeding or prior to liver biopsy: vitamin K
10mg slowly intravenously
Rapid correction may be achieved by infusion of
prothrombin complex concentrate
Liver Disease
1. Biliary obstruction results in impaired absorption of vitamin K & therefore
decreased synthesis of vitamin K-dependent factors
2. With severe hepatocellular disease, there are reduced levels of factor V &
fibrinogen & increased plasminogen activator
3. Functional abnormality of fibrinogen (dysfibrinogenaemia) is found in many
patients
4. Decreased thrombopoietin production from the liver contributes to
thrombocytopenia
5. Hypersplenism associated with portal hypertension frequently results in
thrombocytopenia
6. Disseminated intravascular coagulation (DIC) may be related to release of
thromboplastins from damaged liver cells & reduced concentration of
antithrombin, protein C & α₂-antiplasmin
7. The net haemostatic imbalance in liver disease may be prothrombotic rather
than haemorrhagic
Disseminated intravascular coagulation
(DIC)
Widespread inappropriate intravascular deposition of
fibrin
Leads to consumption of coagulation factors & platelets
Consequence of disorders that release pro-coagulant
material into the circulation or cause endothelial damage
or platelet aggregation
Associated with fulminant haemorrhagic or thrombotic
syndrome with organ dysfunction
Main clinical presentation is with bleeding, but 5-10% of
patients manifest thrombotic lesions e.g gangrene of limbs
Pathogenesis of DIC
Key event is increased activity of thrombin in the circulation
May come from tissue factor (TF) release from damaged tissues
on tumour cells or from up-regulation of TF on circulating
monocytes or endothelial cells in response to pro-inflammatory
cytokines (e.g IL1, TNF, endotoxin)
DIC may be triggered by entry of pro-coagulant material into
the circulation in the following situations: severe trauma,
amniotic fluid embolism, premature separation of the placenta,
widespread mucin-secreting adenocarcinomas, acute
promyelocytic leukaemia (t(15;17)), liver disease, severe
falciparum malaria, haemolytic transfusion reaction & some
snake bites
Pathogenesis of DIC
DIC may also be initiated by widespread endothelial damage &
collagen exposure (e.g endotoxaemia, gram negative & meningococcal
sepsis, septic abortion), certain virus infections & severe burns or
hypothermia
Thrombin produces large amounts of circulating fibrin monomers
which form complexes with fibrinogen & interfere with fibrin
polymerization
The combined action of thrombin & plasmin causes depletion of
fibrinogen & all coagulation factors
Intramuscular thrombin also causes widespread platelet aggregation
in the vessels
The bleeding problems in DIC are compounded by thrombocytopenia
caused by consumption of platelets
Pathogenesis of DIC
Clinical features
Dominated by bleeding, particularly from venepuncture
sites or wounds
There may be generalised bleeding in the GIT, oropharynx,
into the lungs, urogenital tract & in obstetric cases, vaginal
bleeding may be severe
Microthrombi may cause skin lesions, renal failure,
gangrene of the fingers or toes or cerebral ischaemia
Some patients may develop sub-acute or chronic DIC,
especially with mucin-secreting adenocarcinoma
Compensation by the liver may render some of the
coagulation tests normal
Laboratory findings
Tests of haemostasis
1. Platelet count is low
2. Fibrinogen concentration low
3. Thrombin time is prolonged
4. High levels of fibrin degradation products such as D-dimers
are found in serum & urine
5. The PT & APTT are prolonged in the acute syndrome
Blood film examination
Haemolytic anaemia (microangiopathic)
RBCs show prominent fragmentation because of damage
caused when passing through fibrin strands in small vessels
Thank you!
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