Bleeding disorders

OSUNKALU V.O
 Normal haemeostasis
• The normal haemostatic response to vascular
damage depends on a closely linked
interaction between the blood vessel wall,
circulating platelets and blood coagulation
factors.
• Primary haemostasis is the initial stage during
which vascular wall and platelets interact to
limit the blood loss from damaged vessel.

• During secondary haemostasis, a stable fibrin

clot is formed from coagulation factors by
enzymatic reactions.
• Although formation of blood clot is necessary
to arrest blood loss, ultimately blood clot
needs to be dissolved to resume the normal
blood flow.
• The process of dissolution of blood clot is
called as fibrinolysis
 Blood vessel wall in homeostasis
• Vasoconstriction of small vessels following
injury.
• Release of vWF that binds platelets to
subendothelium
• Release of platelet activating factors to induce
aggregation of platelets
• Release of tissue factor that activates the
coagulation cascade
 Platelet function in homeostasis

• Platelet function falls into three:

• Adhesion –binding of platelets to collagen and vascular sub
endothelium( which are exposed during vascular injury) is which facilitated by
plt cell membrane glycoproteins -
(glycoproteins Ia – attaches plts to collagen , glycoproteins Ib and IIb- IIIa- attach to VVF and then to vascular
subendothelium )

• Platelet release- release of ADP from dense granules in the platelet

promotes platelet aggregation
- Thromboxane A2 (TxA2 )also induces aggregation of other platelets and local
vasoconstriction

• Aggregation- platelet-platelet aggregation and cross - linking of platelets with

fibrinogen (through glycoprotein IIb –IIIa)
 Coagulation cascade
• A number of coagulation proteins (factors)
participate in coagulation reactions, which
ultimately lead to the formation of a fibrin clot.

• According to the International System

of Nomenclature, coagulation factors are
designated by Roman numerals (I to XIII).
 Coagulation proteins can be divided into
following categories:
• Fibrinogen (Factor I);
• Serine proteases:
(a) Vitamin K-dependent Factors—II, VII, IX, X,
(b) Contact factors—XI, XII,
• Cofactors—V, VIII, tissue factor (F III)
• Transglutamases -Factor XIII
 Generation of thrombin follows 2 phases:
• Initiation phase (initiated by tissue factor) -
small amounts are generated (picomolar
concentrations) This prepares for the 2nd phase.
• Amplification -larger thrombin burst than
produced during the initiation phase
(a million - fold higher concentration) initiates
significant fibrin polymerization.
 Bleeding disorders
• Result from:
• Vascular disorders( abnormality of vascular
wall)
• Platelets,( thrombocytopenia or defective
platelet function
• Coagulation factors.(defective coagulation)
 Bleeding terminology

• Petechiae: Tiny pin point areas of haemorrhage (≤ 2 mm in diameter) due to

vascular or platelet disorder.
They usually occur in clusters and do not blanch on pressure.
• Purpura: Areas of haemorrhage ≥ 2 mm but less than 1 cm in diameter.
Appearance depends on age of lesion (red→purple→brown yellow). They
do not blanch on pressure. They occur in vascular or platelet disorder.
• Ecchymosis (Bruise): An area of extravasated blood in skin greater than 1 cm
in diameter. They result from trauma or haemostatic disorder.
• Telangiectasia: These are spots or areas resulting from localised dilated blood
vessels. They blanch on pressure.
• Haematoma: A swelling resulting from a large area of haemorrhage in
subcutaneous tissue or muscle. It does not blanch on pressure. It results
from trauma or coagulation disorder.
• Haemarthrosis: Bleeding into a joint.
 Clinical differentiation between platelet/vascular and coagulation disorders
Parameter Platelet/vascular disorder Coagulation disorder
Commonly affected sex Both sexes but more commonly Male
female
Family history often negative as most cases are Often positive (as most
acquired) cases are hereditary

Previous history of bleeding Not present Present since early

childhood

Petechiae, bleeding gums, Common Rare

epistaxis(mucosal bleeding)
Menorrhagia

Bleeding from skin cuts Persistent Minimal

Recurrence of bleeding from Not seen Characteristic (12–24

the same site hours or days hours after injury
following injury
Deep haematoma (muscle Not seen Common
bleeding),haemarthrosis (joint
bleeding)
 Tests of haemostatic function

• Platelets
-Platelet count
-Bleeding time
• Platelet function
-Platelet function tests( aggregation, PFA-100)
 Vascular disorders
Acquired inherited
Simple easy bruising/purpura simplex Hereditary haemorrhagic telangiectasia

Senile purpura seen in elderly pts>70yrs Connective tissue disorders

seen mainly on dorsal aspects of the forearms and
hands
Atrophy of the supporting
tissues of cutaneous blood vessels
-Ehler Dalos syndrome
-Pseudoxathoma elasticum
Hereditary collagen abnormalities & hyperextensibility
of joints and hyperelastic friable skin. Superficial
bruising and purpura following
minor trauma or after the application of a
tourniquet. Bleeding and poor wound healing
common

Infections(bacterial, viral) -purpura from direct

vascular damage +DIC or by immune complex
mechanism.
Usu associated with meningococci, salmonella,
measles virus, and rickettsial organisms.
Henoch – Schönlein syndrome

Scurvy
-Defecttive collagen synthesis
Steroids, cushings syndrome
-defective vascular supportive tissue
 Platelet disorders
Disorders of platelets include :
• Thrombocytopaenia

• Platelet dysfunction.
• Thrombocytopenia 100,000/cmm (N= 150-
400,000)
• Platelet counts < 50,000
- usually cause bleeding with trauma or surgery
or mild spontaneous bleeding.
• Platelet count <20,000/cmm
-associated with risk of spontaneous, severe
haemorrhage.
Causes of thrombocytopenia

• Decreased production of platelets in bone

marrow(most common)
• Increased peripheral destruction of platelets
• Dilutional thrombocytopaenia
• Sequestration in enlarged spleen.
 Causes of thrombocytopenia
Decreased Increased peripheral Dilutional sequestration
production destruction thrombocytopaenia

•Congenital( rare) •Immune Massive transfusion of Hypersplenism

primary stored blood (more than
•Usually as part of bone -Idiopathic thrombocytopaenic 10 units over a 24 - hour
marrow failure purpura (ITP) period)
-Cytotoxic drugs secondary
-Radiotherapy -Systemic lupus erythematosus
-Aplastic anaemia -Drugs: heparin , quinine,
-Leukaemia quinidine penicillin
-Myelodysplastic -Infections: HIV, malaria,
syndromes hepatitis C virus, Helicobacter
-Myelofibrosis pylori
-Marrow infi ration (e.g.
carcinoma, lymphoma •Non immune
multiple myeloma) -Disseminated intravascular
-Megaloblastic anaemia coagulation(DIC)
-HIV infection -Thrombotic thrombocytopenic
purpura(TTP)
 Increased peripheral destruction
Idiopathic thrombocytopenic purpura(ITP)

• Autoantibodies or immune complexes bind to platelets

and cause their premature peripheral destruction.
• Normal lifespan of a platelet is 7 – 10 days but in ITP
this is reduced to a few hours

• Megakaryocytes are normal or increased in bone

marrow.

• ITP occurs in two forms—acute and chronic.

 Increased peripheral destruction
Idiopathic thrombocytopenic purpura(ITP)

Chronic:

• Platelet autoantibodies (usually IgG) result in the

premature removal of platelets from the circulation by macrophages
of the RES especially the spleen

• Most common cause of thrombocytopenia without anaemia or

neutropenia
• Common in women aged 15 – 50 years M:F 3:1
• Usually idiopathic (primary)
• Thrombocytopenia may occur with other immune dxs e.g SLE, HIV,
CLL.(secondary ITP)
• Petechial haemorrhage, easy bruising and, in women,
menorrhagia.
• Mucosal bleeding (e.g. epistaxes , gum bleeding)
• Bleeding often NOT severe to cause ICH
• Usu no splenomegaly (consider other diagnosis with
fndings of splenomegaly)
• Sensitive tests are able to demonstrate
specific platelet antibodies antibodies on the
platelet surface or in the serum in most
patients.
Treatment
• Steroids (prednisolone)
• Other immunosupressants(e.g. vincristine,
cyclophosphamide, azathioprine,
mycophenolate mofetil or ciclosporin)
• indicated for patients in whom steroids are
contraindicated or who do not respond to
steroids.
Acute idiopathic thrombocytopenic purpura

• Most common in children.

• Follows vaccination and infection such as chickenpox or
infectious mononucleosis in approximately75% of patients
after an interval of 2 to 3 weeks
• Most cases caused by non – specific immune complex
attachments to platelets.
• Spontaneous remissions are usual; Recurrences are
uncommon.
• 5 – 10% of cases ,the disease may become chronic (lasting > 6
months)
Thrombotic thrombocytopenic purpura(TTP)
• Characterised by formation microthrombi in
microcirculation of various organs due to aggregation of
platelets.
• There is deficiency of the metalloprotease (ADAMTS13 )which
breaks down ultra large von Willebrand factor multimers.
- Familial - mutations in the ADAMTS13 gene
- Acquired- development of an inhibitory IgG autoantibody against the
metalloprotease(ADAMTS13)
• Therefore, there is accumulation of of ultra-large vWF
multimers that bind large number of platelets.
• These platelet thrombi are capable of emobilizing to
microvessels contributing to organ ischemia
TTP comprises 5 features:
• Thrombocytopenia.
Bleeding manifestations secondary to severe thrombocytopaenia such as petechiae, ecchymoses, epistaxis and ,
gastrointestinal/genitourinary bleeding

• Microangiopathic haemolytic anaemia

Haemolysis of red cells results from their passage across fibrin strands of microthrombiin circulation. Clinically patients
have pallor and frequently icterus
• Lab features: fragmented RBCs (schistiocytosis)

• Neurologic abnormalities
Altered level of consciousness, seizures, visual field abnormalities, and hemiparesis, which may
terminate in coma

• Renal failure
Haematuria, azotaemia ,protenuria

• Fever.
N.B.↑ LDH in TTP is derived both from ischaemic or necrotic tissue cells and lysed red cells
 Treatment of TTP

• Platetet transfusions are NOT indicated

• Plasmapheresis, FFP
This removes the large molecular weight VWF
multimers and the antibody and provides ADAMTS13
Haemolytic uraemic syndrome (HUS)

• Characterised by triad of acute renal failure

thrombocytopaenia, and microangiopathic haemolytic
anaemia
• Commonly limited to children

• Organ damage is limited to the kidneys.

 Plt function abnormalties
• Hereditary

• Acquired
Hereditary
-Glanzmanns disease- failure of plt aggregation due to def. of
glycoproteins IIb- IIIIa
-Benard Soulier
Deficiency of glycoprotein Ib (attaches plts to VwF and to
subendothelium)
-Grey platelet syndrome- absence alpha granules(contain VwF
and clotting factors)
- δ - storage pool disease -absence of dense granules that
secrete ADP(ADP promotes plt aggregation)
 Acquired
• Drugs
-Aspirin ( most common cause of defective platelet function)
Inhibition of cyclo - oxygenase with impaired thromboxane A 2 synthesis(TxA2
causes plt aggregation)

-Dipyridamole
inhibits platelet aggregation by blocking reuptake of adenosine

-Intravenous agents -abciximab, eptifibatide and tirofiban are inhibitors of

GPIIb/IIIa receptor sites.(plt-plt aggregation, plt fibringen binding)

• Other diseases
-Uraemia
 Coagulation disorders
• Acquired- DIC, vit K deficiency liver dx, Drugs

• Inherited- Haemophilia A, B and vWD

• Acquired coagulation disorders
Disseminated intravascular coagulation (DIC)
An acquired disorder occurring in a wide spectrum of
underlying diseases and characterised by:
(i) Widespread inappopriate systemic activation of coagulation
with formation of microthrombi in small blood vessels
(ii) Bleeding diathesis secondary to depletion of coagulation
factors and platelets
Results from:
• Release of procoagulant material into the
circulation
(severe trauma, amniotic fluid embolism,premature separation of the placenta, widespread
mucin - secreting adenocarcinomas, acute promyelocytic leukaemia liver disease, severe

falciparum malaria, haemolytic transfusioreaction and some snake bites .

• widespread endothelial damage
(endotoxaemia, Gram - negative and meningococcal septicaemia, septic abortion),
severe burns)

• platelet aggregation
Causes of DIC

• Sepsis or severe infections

• Trauma especially of brain or crush injury
• Obstetric conditions: amniotic fluid embolism, abruptio
placentae, septic abortion, eclampsia, intrauterine
• retention of dead foetus
• Malignancy: disseminated solid cancers, acute promyelocytic
leukaemia
• Severe haemolytic transfusion reactions
• Thermal injury- heat stroke, extensive burns
• Snake bite
• Severe liver disease
• Giant haemangioma
 Pathogenesis of DIC

• The key event underlying DIC is increased activity of thrombin in the

circulation that overwhelms its normal rate of removal by natural
anticoagulants.

• intravascular thrombin formation produces large amounts of circulating

fibrin monomers which form complexes with fibrinogen and interfere with fibrin
polymerization

• Intense fibrinolysis is stimulated by thrombi on vascular walls and the release

of split products interferes with fibrin polymerization, thus contributing to the
coagulation defect.

-
Clinical features of DIC

• Bleeding, particularly from venepuncture sites

or wounds
• generalized bleeding( gastrointestinal tract,
the oropharynx, into the lungs, urogenital
tract )
• microthrombi may cause skin lesions, renal
failure, gangrene of the fingers or toes or
cerebral ischaemia. (less frequently)
Investigations
• low platelet count
• low Fibrinogen concentration
• prolonged thrombin time is prolonged.
• High levels of fibrin degradation products
such as D - dimers are found in serum and
urine.
• Prolonged PT and APTT
Blood film in DIC
• Microangopathic haemolytic anaemia
Red cells show prominent fragmentation because of
damage caused when passing through fibrin strands
in small vessels
Treatment
• Treat underlying disease
• Manage complications
Bleeding complications
-fresh frozen plasma
-platelet concentrates
-cryoprecipitate (provides a more -concentrated source of
fibrinogen)
- red cell transfusions
Thrombotic complications(e.g. skin necrosis)
- Heparin or antiplatelet drugs to inhibit the coagulation
process
Vitamin K deficiency

• Fat - soluble vitamin K is obtained from green

vegetables and bacterial synthesis in the gut
• Required for the synthesis of vit K dependent
factors in the liver
• Deficiency of vitamin K is caused by an
inadequate diet, malabsorption or inhibition
of vitamin K by drugs such as warfarin which
act as vitamin K antagonists
Liver disease
• Decreased synthesis of factors II, VII, IX and X.
(vitamin K dependent factors) by liver parenchymal
cells
• Decreased thrombopoietin production from the
liver contributes to thrombocytopenia.
• Hypersplenism associated with portal hypertension
frequently results in thrombocytopenia.
• Disseminated intravascular coagulation (DIC) may
be related to release of thromboplastins
• Impaired removal of activated clotting factors and
increased fibrinolytic activity.
Haemorrhagic disease of the newborn

Usually presents on 2nd to 4th day of life, but

occasionally during the first 2 months
Attributed to:
• Liver cell immaturity
• Lack of gut bacterial synthesis
• low quantities of vitamin K in breast milk
Drugs e.g. Warfarin (overdose)

• Warfarin is associated with a decrease in the functional

activity of factors II, VII, IX and X
• Conversion of these factors to their biologically active
forms involves gamma- carboxylation of glutamic acid
residues in the N - terminal region of these factors
• vitamin K is converted to vitamin K epoxide by
vitamin K epoxide reductase in the process of
carboxylation
• Warfarin interferes with the action of vitamin K
epoxide reductase leading to a functional vitamin K
deficiency.
• Tx-vitamin K, FFP
Heparin overdose

• Heparin inhibits thrombin ( potentiates formation of complexes

between antithrombin and activated serine protease coagulation factors)

-Also impairs platelet function

Tx-protamine sulphate
Inherited coagulation disorders
Haemophilia A
• Most common of the hereditary clotting factor
deficiencies.
• Inheritance is X - linked
• Defect is an absence or low level of plasma
factor VIII.
• Inadequate amounts of thrombin are
generated leading to insufficient clot formation

• 30% -no family history

Clinical Features of haemophilia

• Profuse post – circumcision haemorrhage in infants

• Joint and soft tissue bleeds and excessive bruising .
• Prolonged bleeding occurs after dental extractions
• Haematuria and gastrointestinal haemorrhage
• Recurrent painful haemarthroses(bleeding into joints.) and muscle haematomas
dominate the clinical course of severely affected patients
-can lead to progressive joint deformity and disability if inadequately treated .
• The lower the factor VIII levels the worse the clinical severity clinical severity
• Operative and post -traumatic haemorrhage are life - threatening both in severely
and mildly affected patients
• Haemophilic pseudotumours (large encapsulated haematomas with progressive
cystic swelling from repeated haemorrhage. May occur in muscle planes, large
muscle groups and in the long bones, pelvis and cranium.
- Best visualized by magnetic resonance imaging
Diagnosis

• Clinical HX -Haematomas, haemarthrosis, excessive post-

traumatic bleeding, delayed bleeding
• Presentation in early childhood; family history often +ve (X-
linked recessive)
• Bleeding time, platelet count - normal
• APTT - Prolonged
• • Definitive diagnosis - Factor VIII assay.
• Antenatal diagnosis for carriers
- Chorionic biopsies at 8 – 10 weeks ’ gestation provide
sufficient fetal DNA for analysis.
Mangement of haemophilia A
• Bleeding episodes are treated with factor VIII replacement
therapy(concentrates or recombinant factor VIII)
• Spontaneous bleeding is usually controlled if the patient ’ s
factor VIII level is raised to 30 – 50% of normal
• 1 - Diamino - 8 - D - arginine vasopressin (DDAVP;
desmopressin) provides an alternative means of
increasing the plasma factor VIII level in milder
haemophiliacs (causes factor VIII release from endothelial
cells) and this rise is proportional to the resting level within
30-60min) (IV ,subcut, nasal)
Prophylaxis
• prophylactic factor VIII three times a week has
been found to reduce complications( e.g joint
damage) compared with on demand
treatment
Haemophilia B

Factor IX deficiency
• Also X linked
• Clinical features similar to factor VIII deficiency
• Bleeding episodes are treated with IX
concentrates or recombinant factor IX
vWD

• VWF is produced in endothelial cells and

platelets.
Functions of VWF
- promotes platelet adhesion to
subendothelium
-carrier molecule for factor VIII, protecting it
from premature destruction.
VWD

Reduced level or abnormal function of von

Willebrand factor (VWF)
• Results from a mutations in the gene coding for
VWF
• Types 1- 3.
-Type 1- most common(75%)
-Type 3 associated with more severe bleeding
• Affects both male and females
• Females tend to have more severe disease
Clinical features

• Mucous membrane bleeding (e.g. epistaxes,

menorrhagia),
• Excessive blood loss from superficial
cuts and abrasions,
• Operative and post – traumatic haemorrhage
• Haemarthroses and muscle haematomas
are rare, except in type 3 disease
Lab features
• VWF levels are usually low
• Factor VIII levels are often low.
• Prolonged APTT
• Platelet counts usually normal
Treatment

• DDAVP infusion for those with type 1 VWD.

-releases VWF from endothelial cells 30 min
after intravenous infusion.
• Plasma - derived factor VIII/VWF for very low
VWF levels.