Core Clinical Problem 2- Bleeding
Basic Clinical Science
Haemostatic Mechanisms:
Haemostasis- ‘the stopping of bleeding’ (regulation of blood clotting and response to an injured
vessel).
Haematoma- ‘accumulation of blood in the tissues which can occur as a result of bleeding from any
vessel type’.
Small Vessels (arterioles, capillaries and venules)
 Physiological haemostatic mechanisms are most effective in dealing with injuries to these
vessels.
 Most common source of bleeding in everyday life is from these vessels.
Blood vessel severed  inherent constriction occurs (mechanism
unclear)  endothelial sides are opposed and stick together.
Body usually cannot control bleeding from medium/large sized artery therefore other processes
must also occur:
1. Formation of a platelet plug
2. Blood coagulation (clotting)
Formation of a platelet plug:
Vessel damage

Altered endothelial surface
(underlying connective tissue collagen is exposed)

Platelets adhere to collagen
(Largely via an intermediary (von Willebrand factor (vWF)- plasma protein secreted by endothelial
cells and platelets. vWF forms a bridge between damaged vessel wall and platelets)

Platelets binding causes release of contents of their secretory vesicles
(Including adenosine diphosphate (ADP) and serotonin- induce multiple changes in metabolism, shape
and surface proteins of the platelets- PLATELET ACTIVATION).

Leads to PLATELET AGGREGATION rapidly creating the PLATELET PLUG.

Platelet adhesion synethesises thromboxane A2
Core Clinical Problem 2- Bleeding
(released into extracellular fluid and acts locally to further stimulate platelet aggregation and release
of their secretory vesicle contents).

Fibrinogen
(crucial role in platelet aggregation- forms bridges between aggregating platelets)

Contraction
(platelets contain high level of actin and myosin- stimulated to contract in aggregated platelets.
Strengthens and compresses the platelet plug).

Blood vessels
(vascular smooth muscle is stimulated to contract- decreases blood flow to area and pressure within
vessel).
NB:
The platelet plug does not spread along intact endothelium in both directions due to several
reasons:
1) Adjacent undamaged endothelial cells synthesize and release prostacyclin (PGI2), which is a
profound inhibitor of platelet aggregation.
2) Release nitric oxide, vasodilator and inhibitor of platelet adhesion, activation and
aggregation.
Blood coagulation: Clot formation
Blood coagulation/clotting: ‘transformation of blood into a solid gel called a clot or thrombus
consisting mainly of fibrin.’


Dominant haemostatic defence.
Function is to support and reinforce the platelet plug and to solidify blood in the wound
channel.
Injury to vessel
(disrupts endothelium and allows blood to contact underlying tissue)

Cascade of locally occurring chemical activations
(at each cascade step, an inactive plasma protein or ‘factor’ is converted to a proteolytic enzyme
which catalyzes the generation of the next enzyme in the sequence).

Prothrombin to thrombin
(thrombin catalyzes a reaction in which several polypeptides split from fibrinogen. These remnants
then bind to form:

FIBRIN
(initially a loose mesh of interlacing strands. Strengthened and stabilized quickly by enzymatically
mediated formation of covalent cross-linkages).

Chemical linking
Core Clinical Problem 2- Bleeding
(catalyzed by enzyme known as ‘factor XIIIa’ which is formed from plasma protein factor XIII in a
reaction catalyzed by thrombin).

Thrombin
(exerts a positive feeback on its own formation. Does this by activating various proteins and platelets
in the cascade).

Process of clotting
(erythrocytes and other cells trapped in fibrin meshwork)
NB:




Activated platelets are essential as several cascade reactions take place on the surface of
platelets.
Thrombin an important stimulator of platelet activation.
Activation causes them to display specific plasma membrane receptors that bind several of
the clotting factors, which permits the reactions on the surface to take place.
Plasma calcium required at various steps in the clotting cascade
Two Pathways:
Intrinsic
Vessel damage

Exposed collagen
contact
activation
Extrinsic
Vessel damage

Subendothelial cells exposed to blood
Tissue factor
VIIa
  
XII XIIa
  VII

 



XIXIa











XIIXaIX 




VIIIVIIIa Activated

 
Platelets





XXa  X



VVa 

Activated platelets



Prothrombin  Thrombin

Core Clinical Problem 2- Bleeding
Intrinsic pathway





Factor XII becomes activated to factor XIIa when it comes into contact with certain surfaces
including collagen fibers underlying damaged endothelium. It is a complex process requiring
several other plasma proteins.
Factor XIIa then catalyzes the activation of factor XI to factor XIa, which activates factor IX to
factor IXa.
Factor IXa then activates factor X to factor Xa.
This is the enzyme that converts prothrombin to thrombin.
Factor VIIIa is also a co-factor in the factor IXa-mediated activation of factor X.
Extrinsic pathway





Initiates the clotting cascade.
Begins with the protein ‘tissue factor’ which is located on the outer plasma membrane of
various tissue cells including fibroblasts and other cells in the wall of blood vessels below
the endothelium.
Blood exposed to these subendothelial cells when vessel damage disrupts the lining.
Tissue factor then binds a plasma protein ‘factor VII’, which is activated to factor VIIa.
The complex of tissue factor and XIIa on the plasma membrane catalyzes the activation of
factor X, along with the activation of factor IX.
Two pathways merge at factor Xa, which catalyzes the conversion of
prothrombin to thrombin and then catalyzes the formation of fibrin.
NB:
Liver plays an important role in clotting. Therefore persons with liver disease often have bleeding
problems:
 It is the site of production for many of the plasma clotting factors.
 It produces bile salts which are important for intestinal absorption of the lipid-soluble
substance vitamin K. The liver requires this vitamin to produce prothrombin and several
other clotting factors.
Abnormalities of haemostasis:



Thrombocytopenia (low platelet count).
Haemophilia (heritable loss of factor VIII (A) or IX (B) leading to slow coagulation and
extensive haemorrhage).
Hypercoagulable states include: factor V Leiden, antiphospholipid syndrome and
thrombocytosis (raised platelet count).
Blood Loss


10% change in blood loss produces no change in blood pressure.
20-30% loss can cause shock- not usually life-threatening.
Core Clinical Problem 2- Bleeding


30-40% loss produces severe or irreversible shock (50-70mmHg drop in BP).
Resp rate is a more sensitive indicator of blood loss than pulse rate or BP.
Immediate Responses to Haemorrhage:
1. Arterial Baroreceptor Reflex
 Consists of the carotid sinuses and the aortic arch baroreceptors.
 Highly sensitive to stretch-directly related to BP. Afferent neurons travel from them to the
brainstem + provide input to the neurons of CV control centres there.
 In blood loss, as the arterial pressure decreases, the discharge rate of the baroreceptors
decreases also this has several effects:
1. Increase HR due to increase sympathetic activity and decreased parasympathetic.
2. Increased ventricular contractility due to increased sympathetic activity to the
arterioles.
3. Increased sympathetic activity to the arterioles causing increased arteriolar
constriction.
4. Increase venous constriction due to increased sympathetic activity to the veins.
NB: the baroreceptor reflex is ONLY for short-term regulation of arterial BP, as it is an
immediate response to deviation from normal arterial BP. However, if the arterial BP deviates
from its normal point for a few days then the arterial baroreceptors adapt to this new level.
2. Autotransfusion
 Movement of interstitial fluid into capillaries.
 This occurs because the drop in BP and increase in arteriolar constriction, decrease capillary
hydrostatic pressure- favouring the absorption of interstitial fluid.
 Can restore body to normal levels within 12-24 hrs after a moderate haemorrhage.
Both these two immediate mechanisms work so efficiently that losses of as much as 1.5L (approx.
30% BV) can be sustained with only slight reductions of mean arterial pressure or cardiac output.
Core Clinical Problem 2- Bleeding
Clinical Science
Bleeding Disorders Overview
After injury, 3 processes halt bleeding:
 VASOCONSTRICTION.
 GAP-PLUGGING BY PLATELETS,
 COAGULATION CASCADE.
Pattern of bleeding (is important):
 Vascular and Platelet disorders lead to prolonged bleeding from cuts, bleeding into the skin
(easy bruising and purpura), and bleeding from mucous membranes (eg. Epistaxis, bleeding
from gums, menorrhagia).
 Coagulation disorders cause delayed haemarthroses and muscle haematomas.
Causes: Acquired, Vit K deficiency, severe liver disease, anticoagulants, long-term antibiotics etc…
Symptoms (vary depending on the disorder)
 Haemarthrosis.
 Excessive bruising
 Heavy bleeding
 Menorrhagia.
 Epistaxis.
Signs/tests:
 Blood count and film (show the number and morphology of the platelets and any blood
disorder eg. Leukaemia or lymphoma). Normal platelet is 150-400 x 109/L
 Bleeding time (measures platelet plug formation in vivo).
 Coagulation tests.
 Prothrombin time (PT)- normal is 16-18secs and is prolonged with factors VII, X, V, II or I,
liver disease or if patient is on warfarin.
 Activated Partial Thromboplastin Time (APTT) or PTT- normal is 30-50s and is prolonged
with deficiencies to one or more of the following factors: XII, XI, IX, VIII, X, V, II or I (NOT
FACTOR VII).
 Thrombin Time- normal is 12s and prolonged by fibrinogen deficiency, dysfibrinogenaemia
(normal level of fibrin but abnormal function) or inhibitors such as heparin or FDPs.
 Factor assays- to confirm coagulation defects.
 Special tests of coagulation
Treatment (depends on the disorder)
 Factor replacement.
 Fresh frozen plasma transfer.
 Platelet transfusion.
 Other therapies.
Core Clinical Problem 2- Bleeding
Complications:
 Bleeding in the brain.
 Severe bleeding (usually from GI tract or injury)
Vascular Disorders:
Type
Congenital
Acquired
Allergic
Drugs
Others
Examples
Hereditary haemorrhagic telangiectasia.
Connective Tissue Disorders (Ehlers-Danlos
syndrome, osteogenesis imperfecta, Marfan’s
syndrome etc…).
Severe infections: septicaemia, meningococcal
infections, measles, typhoid.
HSP
Autoimmune disorders (SLE, RA)
Steroids
Sulphonamides
Senile purpura
Easy bruising syndrome
Scurvy
Factitious purpura.
All the vascular disorders are characterized by easy bruising and bleeding into the skin. Lab tests
including bleeding time are normal.
Hereditary haemorrhagic telangiectasia:
 Rare disorder with autosomal dominant inheritance.
 Characteristic red spots due to dilatation of capillaries and small arterioles, which blanch on
pressure in the skin and mucous membranes, particularly nose and GI tract.
 Recurrent epistaxis and chronic GI bleeding are the major problems and may cause chronic
iron deficiency anaemia.
Easy Bruising Syndrome:
 Common benign disorder occurring in otherwise health women.
 Characterised by bruises on the arms, legs and trunk with minor trauma, possibly due to
skin vessel fragility.
 May give rise to the suspicion of a serious bleeding disorder.
Henoch-Schonlein Purpura:
 Type III hypersensitivity reaction that is often preceded by an acute upper respiratory tract
infection.
 Purpura mainly seen on the legs and buttocks.
 Abdo pain, arthritis, haematuria and glomerulonephritis also occur.
 Recovery usually spontaneous but some people develop renal failure.
Core Clinical Problem 2- Bleeding
Platelet Disorders
 Bleeding due to thrombocytopenia or abnormal platelet function is characterized by
purpura and bleeding.
Platelet Count
109/L
>500 x
500-100 x 109/L
100-50 x 109/L
50-20 x 109/L
<20 x 109 /L
Disorder
Haemorrhage or Thrombosis
No clinical effect
Moderate haemorrhage after injury
Purpura may occur. Haemorrhage after injury
Purpura common. Spontaneous haemorrhage
from mucous membranes. Intracranial
haemorrhage (rare).
Examples:
Thrombocytopenia:
Causes:
1. Impaired Production:
- Bone Marrow failure eg. Megaloblastic anaemia, Leukaemia, Myeloma, Myelofibrosis,
Solid tumour infiltration, Aplastic anaemia: drugs, chemicals, viruses, paroxysmal
nocturnal haemoglobinuria.
2. Excessive Destruction:
- Immune eg. AITP, post-transfusion purpura, alloimmune neonatal thrombocytopenia,
secondary immune.
- Sequestration eg. Hypersplenism.
- Dilutional eg. Massive transfusion.
- Other eg. DIC, TTP, Haemolytic Uraemic Syndrome.
Underlying cause may be revealed by history and examination, however a bone marrow
examination will show whether the numbers of megakaryocytes are reduced, normal or increased,
and will provide essential information on morphology.
Core Clinical Problem 2- Bleeding
Autoimmune (idiopathic) thrombocytopenic purpura (AITP)
The thrombocytopenia is due to immune destruction of platelets. The antibody-coated platelets are
removed following binding to Fc receptors on macrophages.
Acute
Chronic
Epidemiology
Children
Adult women
Cause
Following viral infection
Usually idiopathic but may occur in association
with other autoimmune disorders.
Platelet autoantibodies detected in 60-70%.
Features
Haemorrhage is rare. Normally
Haemorrhage is rare. Normally easy bruising,
easy bruising, purpura, epistaxis purpura, epistaxis and menorrhagia. O/E
and menorrhagia.
normal except for evidence of bleeding,
O/E normal except for evidence
of bleeding,
Investigations Thrombocytopenia on blood
count. Normal or increased
megakaryocytes in the bone
marrow.
Thrombocytopenia on blood count. Normal or
increased megakaryocytes in the bone marrow.
Treatment
Spontaneous remissions are rare. Aims of
treatment:
1. Reduce production of platelet
autoantibodies.
2. Removal of antibody-coated platelets.
Initial treatment is 40-60mg of prednisolone
daily.
 22% have complete response (no
further treamtnet).
 60% have partial response (half of
these may require small doses of steroid
or no further treatment) the other half
and the remaining 20% fail to respond
to steroids at all.
 They relapse and require splenectomies.
 90% response rate to splenectomies,
although 30% of responders eventually
relapse.
 IV Ig produces a rapid rise in platelets.
Usually remits spontaneously.
Treatment with steroids or
high-dose IV Ig is required only
when platelet count <20 x
109/L.
Core Clinical Problem 2- Bleeding
Usually transient but can be useful in
patients with acute haemorrhage and in
preparing patients for splenectomy.
Other immune thrombocytopenias:
Heparin-induced thrombocytopenia:
 Uncommon complication of heparin therapy.
 Usually occurs 5-14 days after first heparin exposure.
 Immune response against heparin/platelet factor 4 complexes.
 Problem occurs left often with LMW heparin.
 Paradoxically associated with severe thrombosis.
 If diagnosed ALL FORMS OF HEPARIN should be discontinued.
 Often difficult to diagnose as patients on heparin tend to be very sick and may be
thrombocytopenic for other reasons.
Fetomaternal alloimmune thrombocytopenia:
 Fetomaternal incompatibility for platelet-specific antigens, usually for HPA-1a.
 Platelet equivalent of haemolytic disease of the newborn.
 The mother is HPA-1a negative and produces antibodies, which destroy the HPA-1a positive
fetal platelets.
 Self-limiting after delivery, but platelet transfusions may be required initially to prevent or
treat bleeding associated with severe thrombocytopenia.
 Severe bleeding ie. Intracranial haemorrhage may occur in utero.
 AN treatment of mother with platelet transfusions given directly to fetus, has been effective
in severe cases.
Post-transfusion purpura (PTP):
 Rare, occurring 2-12 days after a blood transfusion.
 Associated with a platelet-specific alloantibody, usually anti-HPA-1a in a HPA-1a-negative
individual.
 Normally occurs in females who have been previously immunized in pregnancy or blood
transfusion.
 Self-limiting, but high dose Ig can limit the period of thrombocytopenia.
Thrombotic Thrombocytopenic Purpura (TTP)
Rare, but very serious condition. Platelet destruction leads to profound thrombocytopenia.
Pathophysiology: Due to endothelial damage associated with the presence in the circulation of
very-high-molecular-weight multimers of vWF which accumulate due to the absence of a protease
responsible for their degradation.
Core Clinical Problem 2- Bleeding
Symptoms: Florid purpura, fever, fluctuating cerebral dysfunction and haemolytic anaemia with
red cell fragmentation, often accompanied by renal failure.
Signs: Coagulation screen is usually normal but lactic dehydrogenase (LDH) levels are markedly
raised.
Cause: Not well understood.
Associated with: Pregnancy, oral contraceptives, SLE, infection and drug treatment.
Treatment: Plasma exchange using cryoprecipitate-depleted FFP. Must are also treated with
prednisone and low-dose aspirin.
Prognosis: If left untreated, mortality of 90%. Recurrent and relapsing TTP occurs.
Platelet Function Disorders
Platelet count is normal or increased and bleeding time is prolonged.
Acquired Platelet Function Defect:
Examples: 1. Myeloproliferative disorders.
2.Uraemia and liver disease.
3. Paraproteinaemias.
4. Drug-induced, such as by aspirin or other platelet inhibitory drugs.
Risk Factors: Long-term use of anti-inflammatories eg. Aspirin and ibuprofen. Some antibiotics.
Causes: Idiopathic, multiple myeloma and renal failure.
Symptoms: Above symptoms + haematuria, GI bleeding, haematemesis, purpura and petechiae.
Investigations/Tests: As above.
Treatment:
1. Bone marrow disorders treated with: platelet transfusions (if low), plasma pheresis (if high)
or chemotherapy to treat the condition.
2. Renal failure- treat with dialysis or desmopressin.
3. If caused by medication, stop medication.
Congenital Platelet function defects
Pathophysiology: Cause reduced platelet function even though there are normal numbers. Usually
have a FH of a bleeding disorder causing prolonged bleeding after minor cuts or surgery and easy
bruising.
Core Clinical Problem 2- Bleeding
Examples:
1. Bernard-Soulier syndrome: lack of platelet membrane glycoprotein 1b, the binding site for
vWF. Causes a failure of platelet adhesion and moderate thrombocytopenia.
2. Glanzmann’s thrombasthenia is a condition caused by lack of platelet membrane
glycoprotein IIb/ IIIa complex resulting in defective fibrinogen binding and failure of
platelet aggregation.
3. Platelet storage pool disorder: caused by the faulty storage of substances inside platelets
(they are usually released to help platelets function properly).
No specific treatment for these disorders. Patients should avoid taking aspirin and NSAIDs. Patients
who have severe bleeding may need platelet transfusions.
Congenital Protein C or S Deficiency








Inherited disorder.
Causes abnormal clotting.
About 1 in 300 have a normal and an abnormal gene for protein C deficiency.
Protein S deficiency occurs in about 1 in 20,000 people.
If you have this condition you are more likely to develop clots. Same symptoms as DVT.
You can be tested and will show a lack of either of these proteins.
Heparin/Warfarin are used to thin blood, as treatment.
Possible complications: childhood stroke, recurrent miscarriage, recurrent clots in the legs,
PE.
Core Clinical Problem 2- Bleeding
Coagulation Disorders



Inherited or acquired.
Inherited are uncommon and usually involve deficiency of one factor only.
Acquired occur more frequently and almost always involve several coagulation factors
Inherited
II
Factor Deficiency
V
VII
X
Large
glycoprotein.
Encoded on
chromosome 1
and produced
in hepatocytes
and
megakaryocyt
es.
Vitamin-K
dependent
glycoprotein
and encoded
on
chromosom
e 13.
Vitamin-K
dependent
protease
and is the
most
important
activator of
prothrombi
n. Located
on Ch13 and
activated in
the liver.
Epidemiology RARE. 1 in 2
million. Complete
deficiency may be
incompatible with
life.
Rare. 1 in 1
million.
Presents in
childhood. M:F
= 1:1.
1 in 500,000. Frequency
of severe
deficiency is
1 in 1
million.
Most
heteroztgot
es don’t
have
symptoms,
but some
having sig.
bleeding
tendency,
Common in
caucasian
popn. Most
commonly
severe in
Asians, but
asymptomati
c.
Acquired or
Inherited?
Inherited..
Both
Inherited
Pharma
Vitamin-Kdependent
carboxylase
synthesized in the
liver.
Activated by factor
Xa on the surface of
platelets.
Normally acquired
(rarely inherited)
Inherited.
XII
Core Clinical Problem 2- Bleeding
Cause/s
Lack of Vit K due
to: long-term
antibiotics, bile
duct obstruction or
poor absorption
from the intestines.
Anti-coagulants.
Some babies born
with it.
Inheriting a
defective
Factor V gene
or by acquiring
an antibody
that interferes
with normal
factor V (eg.
after giving
birth).
Lack Vit K,
severe liver
disease and
use of drugs
that prevent
clotting.
Symptoms
Most common
bleeding
manifestations are:
haemarthrosis and
muscle
haematoma.Umbili
cal cord bleeding
has also occurred.
Similar to
others.
Poor
correlation
between
levels of
factor VII
and wide
variety of
bleeding
manifestatio
n.
Epistaxis
very
common.
Menorrhagi
a in 50% of
women.
Infants
watched
closely for
risk of ICH.
Often
asymptomati
c.
?associated
with
thrombotic
events but
no real
evidence.
Investigation
/s
PT and APTT will
be prolonged but
this may be
minimal and is
reagent depedent.
Factor II assay.
Factor V assay
confirms it.
Normal
thrombin time.
Prolonged PTT
and PT. Factor
VIII assay
should be
carried out to
excluded
combined
deficiency.
PT
prolonged,
all other
tests normal.
Factor VII
assay.
PT and
APTT are
prolonged.
Confirmed
deficiency
by factor X
assay.
Unexpected
prolonged
APTT in presurgical
screening.
Treatment
No products
liscenced for use in
prothrombin
deficiency but
several factor
concentrates
contain factor II.
In absence of these,
FFP is a potential
source.
FFP is
treatment of
choice
(preferably
virallyinactivated) as
there are no
FV-contained
concentrates.
Platelet
People with
heterozygou
s deficiency
do not have
an abnormal
bleeding
risk.
Recombinan
t factor VIIa
is treatment
Half-life of
infused FX
is 60 hours.
Prothrombi
n complexes
contain FX
and are
thought to
be effective.
Thrombotic
Core Clinical Problem 2- Bleeding
transfusions
may be of
benefit.
of choice.
Short halflife
therefore
needs to be
given every
2-4 hours.
risk so use
with
caution.
Children
with
repeated
joint bleed
may benefit
from
prophylaxis
1 or 2 a
week. FFP is
an
alternative.
Inherited Coagulation disorders:
The main inherited coagulation disorders that lead to abnormal bleeding are: Haemophilia A,
Haemophilia B and von Willebrand’s Disease.
Bleeding Time
PT
APTT
VII:C
vWF
Haemophilia A
Normal
Normal
Increased +
Decreased ++
Normal
vWD
Increased
Normal
Increased +/Decreased
Decreased
Vitamin K deficiency
Normal
Increased
Increased
Normal
Normal
Haemophilia A
Prevalence: 1 in 5000 of male population. Inherited as a X-linked disorder. All daughters of people
with haemophilia are carriers and the sons are normal. High rate of new mutations (30% no FH).
Clinical Features (depend on level of VIII:C)
 <1%: Frequent spontaneous bleeding from early life. Haemarthoses are common and may
lead to joint deformity and crippling if adequate treatment not given. Bleeding into muscles.
 1-5%: Severe bleeding following injury and occasional apparently spontaneous episodes.
 >5%: Mild disease, usually only bleeding after injury or surgery. Diagnosis often delayed to
late on in life.
Lab Findings: See above.
Treatment: IV infusion of factor VIII concentrate.
 Minor bleeding: factor VIII:C level should be raised to 20-30%.
Core Clinical Problem 2- Bleeding







Severe bleeding: factor VIII:C should be raised to at least 50%.
Major surgery: factor VIII:C should be raised to 100% preop and maintained above 50%
until healing has occurred.
Factor VIII has a half-life of 12 hours therefore must be administered at least twice daily to
maintain required therapeutic level.
Recombinant factor VIII is the treatment of choice, HOWEVER, due to economic constraints
and limited capacity to produce this, patients are still offered plasma-derived concentrates.
Majority of severely affected patients are given prophylaxis 3x a week in childhood to
prevent permanent joint damage.
Desmopressin (0.3µg/kg/12h IVI over 20 mins) raises factor VIII levels and may be
sufficient in mild disease.
AVOID NSAIDS and IM injections.
Complications:
 At least 10% of people with haemophilia A have antibodies to factor VIII:C. Management
therefore may be difficult as even extremely high doses may not produce a rise in plasma
level. Some factor IX concentrates contain activated factors, which may ‘bypass’ the inhibitor
and stop the bleeding. Recombinant factor VIIa also has this bypassing potential.
Haemophilia B



Factor IX deficiency inheritance and clinical features are identical to Haemophilia A except
the incidence is only 1 in 30,000 males.
Half-life is longer at 18 hours.
Treated with factor IX concentrates, recombinant factor IX now available and prophylactic
doses given twice a week. DDAVP is ineffective.
Von Willebrand’s disease (vWD)
Aetiology: Defective platelet function as well as factor VIII:C deficiency and both are due to a
deficiency or abnormality of vWF. vWF gene is located on chromosome 12 and numerous
mutations have been identified.
3 Types:
 Type 1: characterized by mild reduction in vWF and inherited as an autosomal dominant.
 Type 2: a decrease in the proportion of high-molecular-weight multimers, and is aut. Dom.
 Type 3: recessively inherited and patients have barely detectable levels of factor vWF.
Parents often phenotypically normal.
Clinical Features:
 Variable.
 Type 1 and 2 patients usually have mild clinical features. Bleeding follows minor trauma or
surgery, and epistaxis and menorrhagia often occur. Haemarthroses are rare.
 Type 3 have more severe bleeding but rarely experience the joint and muscles bleeds seen in
Haem A.
Core Clinical Problem 2- Bleeding
Lab Findings: See above table.
Treatment:
 Depends on severity.
 May be similar to that of haemophilia including use of DDAVP where possible.
 Intermediate purity factor VIII or vWF concentrates should be used to cover surgery in
patients who require replacement therapy especially in type 3.
 Cryoprecipitate should be avoided because of the greater risk of transfusion-transmitted
infection (since it is not a virally-inactivated product).
Acquired Coagulation Disorders
1. Vitamin K deficiency:
Aetiology: Necessary for the carboxylation of glutamic acid residues on coagulation factors II, VII,
IX and X and on proteins C and S. Without it these factors cannot bind calcium and form complexes
with PF-3 to carry out normal function.
Causes:
 Inadequate stores: ie. Haemorrhagic disease of newborn (see below) and severe
malnutrition.
 Malabsorption of Vit K.
 Oral anticoagulant drugs (vit K antagonists).
Lab Findings: See table above.
Treatment: Minor bleeding is treated with Vit K1 IV. Admin Vit K to all neonates.
2. Liver Disease:
May cause a number of defects in haemostasis:
 Vit K deficiency.
 Reduced synthesis.
 Thrombocytopenia.
 Functional Abnormalities.
 DIC.
Core Clinical Problem 2- Bleeding
3. Disseminated Intravascular Coagulation
Causes:
 Malignant disease.
 Septicaemia.
 Haemolytic transfusion reactions.
 Obstetric causes.
 Trauma, burns, surgery.
 Other infections.
 Liver disease.
 Snake bite.
Clinical Features:
 Underlying disorder normally obvious.
 Acutely ill and shocked.
 Varies from no bleeding to profound haemostatic failure with widespread haemorrhage.
 Bleeding may occur from: mouth, nose and VP sites.
 Thrombotic events may occur as a result of vessel occlusion by fibrin and platelets. Any
organ may be involved, but the skin, brain and kidneys are most often affected.
Core Clinical Problem 2- Bleeding
Investigations:
 In severe cases with haemorrhage: PT, APTT and TT are usually very prolonged and the
fibrinogen level markedly reduced.
 Severe thrombocytopenia.
 Blood film may show fragmented RBCs.
 In mild cases: increased synthesis of coag. Factors and platelets may result in normal PT,
APTT, TT and platelet counts.
Treatment:
 Underlying condition treated.
 Maintenance of BV and tisse perfusion.
 Transfusions of platelet concentrates, FFP, cryoprecipitate and RC concentrates is indicated
in patients who are bleeding.
 Use of heparin to prevent coag is rarely indicated.
NB:
Example of Vit K deficiency:
Haemorrhagic disease of the newborn
 A bleeding disorder that develops shortly after birth.
 Due to a Vitamin K deficiency.
 Babies have low levels of vitamin K for several reasons:
 It doesn’t move easily across the placenta from mother to baby.
 Also there isn’t much in breast milk.
Causes:
 If the baby is not given a preventative Vit K vaccine at birth (sometimes it is given orally
which is not as effective and should be given more than once).
 The mother takes anti-seizure drugs.
3 categories of condition:
1) Early onset (very rare), that occurs during the first hours of birth and certainly within 24hrs.
Use of anti-seizure drugs during pregnancy is a common cause.
2) Classic onset is in breastfed babies within the first week of birth, that didn’t receive a Vit K
vaccine. Also rare.
3) Late onset seen in infants older than 2 weeks and up to 2 months.
Babies with the following are more likely to develop it:
 Alpha1-antitrypsin deficiency.
 Biliary atresia.
 Coeliac disease.
 Cystic fibrosis.
 Diarrhoea.
 Hepatitis.
Core Clinical Problem 2- Bleeding
Symptoms (most common areas of bleeding):
o A boy’s penis if he’s been circumcised.
o Belly button area.
o GI tract.
o Mucous membranes.
o Places where there has been a needle stick.
There may also be:
o Blood in the urine.
o Bruising.
o Raised lump on the baby’s head.
Tests:
Blood clotting tests.
Diagnosis confirmed if the vit K vaccine stops the bleeding and Prothrombin time (blood clotting
time) is within normal limits.
Prognosis:
Worse for babies with late onset disease as more intracranial bleeding occurs.
Core Clinical Problem 2- Bleeding
Approach to bleeding:
-Is there an emergency?
 Is the patient about to exsanguinate?
 Is there hypovolaemia?
 Is there CNS bleeding?
-Why is the patient bleeding?
 Is it normal given the circumstances (eg. Surgery, trauma…) or do they have a bleeding
disorder?
 Is there a secondary cause (drugs-warfarin, alcohol, liver disease, sepsis?
 Past or FH of excess bleeding eg. During trauma, surgery, dentistry?
 Is the pattern of bleeding indicative of vascular, platelet or coagulation problems? Are
venepuncture or cannula sites bleeding?
 Is a clotting screen abnormal? Check FBC, platelets, PT, APTT and thrombin time. Consider
D-dimers, bleeding time and a factor VIII assay.
In the case of a bleeding disorder:
 Coagulation tests:
 Prothrombin Time (PT): Thromboplastin is added to test the extrinsic system. PT
normal range (0.9-1.2). Tests for abnormalities in factor I, II, V, VII, X. It is prolonged
by: warfarin, Vit K deficiency, liver disease, DIC.
 Activated partial thromboplastin time (APTT): Kaolin is added to test the intrinsic
system. Tests for abnormalities in Factor I, II, V,VIII,IX, X, XI, XII. Normal range is 3545s. Prolonged by: heparin treatment, haemophilia, DIC, liver disease.
 Thrombin time: Thrombin is added to plasma to convert fibrinogen to fibrin. Normal
range: 10-15s. Prolonged by: heparin treatment, DIC, dysfibrinogenaemia.
 D-dimers: These are a fibrin degradation product, released from cross-linked fibrin
during fibrinolysis. This occurs during DIC, or in the presence of venous
thromboembolism- DVT or PE. D-dimers may also be raised in inflammatory states
eg. With infection or malignancy.
 Bleeding time: This is a test of haemostasis, carried out by making two small incisions
into the skin of the forearm. Normal time <7 minutes. NB: This test is seldom
performed now as results are very operator dependent.
Interpretation:
 Platelets: if low do FBC, film, clotting.
 PT: if long look for liver disease or anticoagulant use.
 APTT: if long, consider liver disease, haemophilia (factor VIII or IX deficiency) or heparin.
Core Clinical Problem 2- Bleeding
Blood Transfusion and Blood Products
Products:
 Whole blood- rarely used. Indications: exchange transfusion; grave exsanguination- use
crossmatched blood if possible if not use universal donor group O Rh-ve changing to
crossmatched asap.
 Red cells- Virtually all the plasma is removed and is replaced by about 100mL of an optimal
additive solution, such as SAG-M, which contains sodium chloride, adenine, glucose and
mannitol. Used to correct anaemia or blood loss. 1 unit increases Hb by 1-1.5g/dL.
 Platelets- not usually needed if not bleeding and count is >20 x 109/L. 1U should increase
platelet count by >20 x 109/L. Used prophylactically to prevent bleeding in patients with
bone marrow failure.
 Fresh frozen plasma (FFP)- use to correct clotting defects: eg. DIC, warfarin overdose where
vitamin K would be too slow, liver disease, thrombotic thrombocytopenic purpura. It is
expensive and carries all the risks of blood transfusion.
 Cryoprecipitate: Obtained by allowing the frozen plasma from a single donation to thaw at 48oC and removing the supernatant. Treat massive bleeds. Treat DIC.
 Human albumin solution- it is produced as 4.5% or 20% protein solution and is for use as
protein replacement. 20% albumin can be used temporarily in the hypoproteinaemic
patient.
Core Clinical Problem 2- Bleeding
Pre-transfusion Compatibility testing:
Blood Grouping:
 ABO and RhD groups of the patient are determined.
Antibody Screening:
 Patient’s serum or plasma is screened for atypical antibodies that may cause a significant
reduction in the survival of the transfused red cells.
 It is tested against red cells from at least two group O donors, expressing a wide range of red
cell antigens, for detection of IgM red cell alloantibodies and IgG antibodies.
 In approximately 10% patients have a positive antibody screening results, in which case,
further testing is carried out using a comprehensive panel of typed red cells to determine
the blood group specificity of the antibody.
Selection of donor blood and crossmatching:
 Donor blood of the same ABO and RhD group as the patient is selected.
 Matching for additional blood groups is carried out for patients with clinically significant red
cell antibodies, for patients who are likely to be multitransfused and at high risk of
developing antibodies eg. Sickle cell disease.
 Crossmatching: (patients without atypical red cell antibodies)- full crossmatch involves
testing the patient’s serum or plasma against the donor red cells suspended in saline in a
direct agglutination test, and also using an indirect antiglobulin test.
 (patients with atypical red cell antibodies)- donor blood should be selected that lacks the
relevant red cell antigen(s), as well as being the same ABO and RhD group as the patient. A
full crossmatch should always be carried out.
Core Clinical Problem 2- Bleeding
Blood Ordering:
 Elective surgery: many hospitals have guidelines for this. For ops where blood is required
only occasionally for unexpectedly high blood loss can be classified as ‘group and save’;
this means that, where the antibody screen is negative, blood is not reserved in advance
but can be made readily available quickly if needed.
 Emergencies: There may be insufficient time for full pretransfusion testing therefore the
options are:
1. Blood required immediately- use 2 units of O RhD neg blood to allow additional
time for lab to group the patient.
2. Blood required in 10-15 mins- use of blood of the same ABO and RhD groups as
the patient.
3. Blood required in 45 minutes- most laboratories will be able to provide fully
crossmatched blood within this time.
Transfusion Reactions:

Serious hazards of Transfusion (SHOT) scheme produced its first report in the UK in 1997.
Commonest errors were from collection and administration (51%). Incorrect blood
component transfused was the most frequent error.
Immunological
Non-immunological
Alloimmunization
Transmission of infection
Incompatibility
Viruses- HAV, HBV, HCV, HIV, CMV, EBV
Red cells- immediate haemolytic transfusion
reactions. Delayed haemolytic transfusion
reactions.
Parasites- malaria, toxoplasmosis…
Leucocytes and platelets- non-haemolytic
(febrile) transfusion reactions.
Bacteria.
Post-transfusion purpura.
Prion-CJD
Poor survival of transfused platelets and
granulocytes.
Circulatory failure due to volume overload.
Graft-versus-host disease.
Iron overload due to multiple transfusions.
Lung injury
Massive transfusion of stored blood may cause
bleeding and electrolyte changes.
Plasma proteins: Urticarial and anaphylactic
reactions.
Physical damage due to freezing or heating.
Thrombophlebitis
Core Clinical Problem 2- Bleeding
Air embolism
All UK blood products are now leucocyte-depleted (white cells <5x106/L) so as to reduce the
incidence of complications such as alloimmunisation to HLA class 1 antigens and febrile transfusion
reactions.
Early complications (within 24hrs):
 Acute haemolytic reactions (eg. ABO or Rhesus incompatibility); anaphylaxis; bacterial
contamination; febrile reactions (eg. From HLA antibodies); allergic reactions (eg. Itch,
urticaria, mild fever); fluid overload; transfusion-related acute lung injury (TRALI)
Delayed complications (after 24hrs):
 Infections (eg. Viruses: hepatitis B/C, HIV; prions; bacteria; protozoa); iron overload; graftversus-host disease; post-transfusion purpura-potentially lethal fall in platelet count 5-7d
post-transfusion requiring specialist treatment with IV immunoglobulin and platelet
transfusions.
Massive blood transfusions: replacement of an individual’s entire blood volume (>10u) within
24hrs. Complications: platelets decrease, calcium decreases, clotting factors decrease,
potassium increases; hypothermia
Anticoagulants
1. Warfarin:
Pharmacology: Possesses ability to interfere with the action of Vitamin K1. Inhibits the
regeneration of vit K1 in the liver from the epoxide form of Vit K. By blocking Vit K generation,
glutamate residues or coagulation factors (II, VII and X) are not adequately carboxylated rendering
them non-functional.
Therefore makes coagulation more difficult. Other proteins inhibited by warfarin include: proteins
C+S (involved in the fibrinolytic system).
Indications: A.fib, artificial heart valves, DVT and PE.
Side-effects: Risk of haemorrhage. (Increased risk when take other anti-coagulants too and if
elderly).
NB: give Vit K in overdose.
2. Clopidogrel:
Pharmacology: Inhibitor of platelet aggregation. Inhibits the binding of adenosine diphosphate
(ADP) to its platelet receptor, and the subsequent ADP-mediated activation of the glycoprotein
Core Clinical Problem 2- Bleeding
complex, thereby inhibiting platelet aggregation. Rapidly absorbed after oral administration with
peak levels occurring approx. 1 hour after dosing.
Indications: Preventions of vascular ischaemic attacks in patients with symptomatic
atherosclerosis. STEMI and NSTEMI. Also as an alternative anti-platelet to people intolerable to
aspirin.
Side-effects: severe neutropenia, TTP, haemorrhage, GI side-effects.
3. Aspirin:
Pharmacology: Anti-platelet effect by inhibiting the production of thromboxane. Inhibits the
enzyme cyclooygenase (however differs from other NSAIDs by acting more on COX-1 than COX-2).
It irreversibly inhibits COX-1.
Indications: Prevention of stroke, heart attacks etc… Also for pain, fever, inflammatory disease
etc…
Side-effects: Main are GI bleeds and ulcers.
4. Dipyridamole:
Pharmacology: Blocks phosphodiesterase, which normally breaks down cyclic AMP. Causes levels
of cyclic AMP to rise, therefore stopping platelets clumping together and causing a blood clot.
Indications: Used in conjunction with aspirin for secondary prevention of stroke.
GI Haemorrhage
Causes of Upper GI haemorrhage:
 Drugs (NSAIDS), Alcohol.
 Varices (10-20%).
 Gastric carcinoma (uncommon).
 Reflux oesophagitis (2-5%).
 Mallory-Weiss syndrome (5-10%).
 Gastric ulcer, duodenal ulcer (50%).
 Haemorrhagic gastropathy and erosions (15-20%).
NB: Other UNCOMMON CAUSES include: hereditary telangiectasia, pseudoxanthoma elasticum,
blood dyscrasias, dieulafoy gastric vascular abnormality, portal gastropathy and aortic graft
surgery with fistula.
Reflux Oesophagitis
Inflammation of the lower oesophagus produced by persistent episodes of reflux. Patients may be
asymptomatic.
Core Clinical Problem 2- Bleeding
Diagnosis: Fibreoptic oesophagoscopy is used to confirm the presence of oesophagitis.
Management: Poor correlation between GORD symptoms and the presence of endoscopic
oesophagitis. Treatment can keep most patients symptom free, but symptoms usually return when
treatment is stopped.
Drugs:
 Antacids eg. Magnesium trisilicate and aluminium hydroxide.
 H2 receptor antagonists eg. Ranitidine- used for acid suppression if the above measures fail
and now they can be obtained over the counter.
 PPIs eg. Omeprazole- produce almost complete reduction of gastric acid secretion and are
the drug of choice for all but mild cases.
 Prokinetic agents eg. Metoclopramide and domperidone are dopamine antagonists.
Occasionally helpful as they enhance peristalsis and speed gastric emptying.
Surgery: For a case where there are severe reflux symptoms confirmed by pH monitoring and with
oesophagitis on oesophagoscopy.
Peptic Ulcer Disease
Epidemiology:
 Duodenal ulcers are 2-3 times more common than gastric ulcers.
 10-15% of the population will suffer from a duodenal ulcer.
 Common in the elderly.
 Geographical variation eg. DUs more common in the North than other parts of the UK.
Pathology:
 Gastric ulcers are found in any part of the stomach, but are most common in the lesser curve.
 Most DUs are found in the duodenal cap.
 Break in the superficial epithelial cells penetrating down to the muscularis mucosa at the
site of the ulcer; there is a fibrous base and an increase in inflammatory cells.
 In DU disease, 95% are infected with H.pylori.
Features:
 Epigastric pain.
 Pain of DU classically occurs at night (as well as during the day) and is worse when the
patient is hungry.
 Both are helped by antacids.
 Nausea.
 Heartburn due to acid regurgitation.
 Complications considered if complain of persistent and severe pain.
 Patients can present for the first time with either a haematemesis or melaena or a
perforation.
 Untreated, the symptoms of a DU are periodic with spontaneous relapses and remissions.
Investigations:
Core Clinical Problem 2- Bleeding



If under 45 years with suggestive symptoms and H.Pylori positive- start eradication therapy.
In older patients- endoscopy or barium studies.
All gastric ulcers must be biopsied.
Management:
 Eradication therapy: all patients with ulcers should have H.pylori eradication therapy.
Successful in approx. 90%. Triple therapy with a PPI along with two antiviotic for 1 week eg.
Omeprazole + metronidazole + clarithromycin.
 Normally also require 3-4 weeks further treatment with a PPI.
 Stop smoking.
 Re-endoscoped at 6 weeks to exclude a malignant tumour.
 If there is: recurrent uncontrolled haemorrhage or perforation, then surgery can be used
(partial gastrectomy or vagotomy). Surgical complications seen occasionally (recurrent
ulcer, diarrhoea and nutritional complications).
Complications:
 Haemorrhage.
 Perforation.
 Pyloric stenosis or obstruction.
Erosive and Haemorrhagic Gastropathy
 Aspirin and other NSAIDs deplete mucosal prostaglandins by inhibiting the COX pathway,
leading to mucosal damage.
 COX-1 and COX-2.
 COX-1 produces the most gastric mucosal damage as it is the constitutive enzyme.
 50% of patients on regular NSAIDs will develop gastric mucosal damage and approx. 30%
will have ulcers on imaging.
 Only a small proportion have symptoms and only 1-2% have a major bleed.
 H.pylori and NSAIDs are independent risk factors for the development of ulcers.
 Alcohol also damages the mucosa and can cause acute erosions.
Management:
 NSAIDs or alcohol should be stopped.
 PPI for established ulcers.
 Little evidence the h.pylori eradication is helpful.
 If stopping the NSAID is not possible then: use one with low GI side-effects, add on a PPI or
COX-2 therapy.
Gastric Carcinoma:
 One of the most common malignant tumours of the GI tract (adenocarcinoma).
 Rare under age of 30 and M>F.
Epidemiology:
 Strong link with H.pylori infection.
Core Clinical Problem 2- Bleeding
Normal gastric mucosa - H.pylori infection - Acute Gastritis  Chronic active gastritis 
Atrophic gastritis  Intestinal metaplasia  Dysplasia  Advanced gastric cancer.

Dietary factors can increase risk. Increased risk after a partial gastrectomy.
Screening:
 Appalling prognosis despite treatment.
 Lead-time bias with earlier diagnosis.
 Early gastric cancer (confined to the mucosa or submucosa) has a 5-year survival of 90%.
Pathology:
 Most occur in the antrum and are almost invariably adenocarcinomas.
Symptoms:
 Epigastric pain.
 Most have advanced disease at presentation.
 Vomiting and severe if tumour near the pylorus.
 Anaemia is common.
 Metastases can occur to: liver, bone, brain and lung.
Signs:
 Nearly 50% have a palpable epigastric mass with abdominal tenderness.
 Often weight loss is only feature.
 Palpable lymph node in the supraclavicular fossa (Virchow’s node) is sometimes found and
signs of mets in up to 1/3.
 Most frequently associated with dermatomyositis and acanthosis nigricans.
Investigations:
 FBC, liver biochemistry.
 Gastroscopy. (Can also take biopsies, 8-10 should be taken from around the ulcer margin
and its base to be sure).
 Barium meal- diagnostic accuracy of up to 90%.
 CT
 USS
Staging:
 TNM classification.
Treatment:
 Surgery (if resectable).
 Chemo (for unresectable lesions). Survival can be prolonged for a few months.
 Palliative care with relief of pain and counseling is essential.
NB: other tumours include: stromal, non-hodgkin’s lymphoma…
Management of acute upper GI bleeding:
Core Clinical Problem 2- Bleeding










History and examination.
Monitor the pulse and BP half-hourly.
Take blood for Hb, U+Es, grouping and crossmatching.
Establish intravenous access- central line if brisk bleed.
Give blood transfusion/colloid if necessary.
O2 therapy for shocked patients.
Urgent endoscopy in shocked patients/liver disease.
Continue to monitor pulse and BP.
Re-endoscope for continued bleeding/hypovolaemia.
Surgery if bleeding persists.
Causes of Lower GI Haemorrhage
 Ischaemic Colitis.
 Carcinoma.
 Polyps.
 Diverticula.
 Colitis (Crohn’s of Ulcerative).
 Haemorrhoids.
 Anal Fissure.
 Solitary ulcer of rectum.
 Meckel’s Diverticulum.
 Angiodysplasia.
Management:
 Most start spontaneously. The few that continue bleeding and are haemodynamically
unstable need resus using the same principles as for upper GI bleeds.
 Surgery is rarely required.
 Diagnosis is made using the history and the following investigations as appropriate:
 PR.
 Proctoscopy.
 Sigmoidoscopy.
 Colonoscopy.
 Barium enema.
 Angiography.