Bleeding, Thrombosis and
Transfusion
Lecture 2
K K Hampton
1. Bleeding
Haemostasis
• Correct balance vital to life.
If blood clots in vessel = thrombosis
If blood fails to clot outside blood vessel =
bleeding disorder
Bleeding
• Coagulation cascade
• Series of proteolytic enzymes that circulate in an
inactive state
• Sequentially activated in a cascade or waterfall
sequence
• Generate key enzyme thrombin that cleaves
fibrinogen, creating fibrin polymerization = clot
Platelets
• Organised anucleate particles
• Responsible for primary haemostasis =
bleeding time
• Adhere to damaged endothelium and
aggregate to form platelet plug that blocks
hole in vessel
• Lack of number or function = bleeding
Patterns of bleeding
• Haemophilia = bleeding into muscles and
joints
• Platelet disorders and von Willebrands
disease = muco-cutaneous bleeding
Muco-cutaneous bleeding
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Easy bruising
Prolonged bleeding from cuts
Epistaxsis
Spontaneous gum bleeding / GI blood loss
Menorrhagia
Bleeding after dental extraction
Bleeding after surgery, trauma, childbirth
Personal history of bleeding
• Unexplained or severe bleeding
• Response to minor haemostatic challenges
• Response to major haemostatic challenges
• Try to determine if severe or mild defect
• Haemophilia or muco-cutaneous?
• Duration: lifelong or recent acquired?
Family history
• Determine if lifelong = congential
• Haemophilia A and B = sex-linked
male affected, females carriers, skips a
generation pattern
Family history
• Determine if lifelong = congential
• Haemophilia A and B = sex-linked
male affected, females carriers, skips a
generation pattern
Haemophilia A
• Severe bleeding disorder, bleeding into
muscles and joints
• Rare, 1 in 10,000 males
• Deficiency of factor VIII
• Treat with factor VIII, now recombinant,
previously plasma derived
• Plasma also contained Hepatits B, C , HIV
• Treatment either on demand or prophylaxsis
Haemophilia B
• Severe bleeding disorder indistinguishable
clinically from haemophilia A
• Incidence 1 in 50,000
• Deficiency of factor XI
• Treat with factor IX (recombinant)
Von Willebrands disease
• Autosomally dominantly inherited usually
mild bleeding disorder
• Muco-cutaneous bleeding
• Incidence up to 1% = common
• Often unrecognised and underdiagnosed
• VW Factor needed for platelets to bind to
damaged blood vessels, so lack VWF =
platelet dysfunction, hence muco-cutaneous
Platelet disorders
• Disorders of number or function
• Number less than 80 X 109/l = increased
bleeding
• Functional defects rare, but remember
drugs, esp aspirin
Acquired bleeding disorders
• Recent onset, not lifelong and no family
history.
• May be generalised bleeding or localised
problem
• Remember drug history
Liver disease
• Site of synthesis of coagulation factors and
fibrinogen
• Liver disease often associated with bleeding
and prolonged prothrombin time
Vitamin K deficiency
• Vitamin K necessary for the correct
synthesis of coagulation factors II, VII, XI
and X.
• Vitamin K fat soluble vitamin, deficiency in
malabsorption, esp obstructive jaundice
• Manifests as prolonged prothrombin time
• Treat with IV vitamin K
Drugs
• Aspirin and clopidogrel affect platelet
function
• Heparin and warfarin affect coagulation
cascade
• Steroids make tissues thin and cause
bruising and bleeding
• Many disease can affect liver, kidneys and
bone marrow
Disseminated intravascular
coagulation (DIC)
• Breakdown of haemostatic balance
• Simultaneous bleeding and microvascular
thrombosis
• Life threatening condition
• Causes: 1sepsis 2 obstetric 3 malignancy
assume sepsis and treat for this if uncertain
consider giving plasma and platelets if
needed
2. Thrombosis
Thrombosis
• Blood in vessels should be fluid
• Thrombosis is blood coagulation inside a vessel
• Not to be confused with appropriate coagulation
when blood escapes a vessel, failure of
coagulation in this situation leads to bleeding
Thrombosis
• Thrombosis can occur in
arterial circulation: high pressure:
platelet rich
venous circulation: low pressure
fibrin rich
Arterial thrombosis
• Coronary circulation = myocardial
infarction
• Cerebral circularion = CVA/ stroke
• Peripheral circulation = peripheral vascular
disease: claudication, rest pain, gangrene
Arterial thrombosis
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Risk factors for atherosclerosis:
Smoking
Hypertension
Diabetes
Hyperlipidaemia
Obesity / sedentary lifestlye
Stress / type A personality
Arterial thrombosis
• Myocardial infarction: diagnosis
History, ECG, cardiac enzymes
• CVA: history and examination, CT scan/
MRI scan
• Peripheral vascular disease: history and
examination, ultrasound, angiogram
Venous thrombosis
• Deep venous thrombosis
swollen, warm, tender leg
• Pulmonary embolus
pleuritic chest pain, breathlessness,
cyanosis, death
Venous thrombosis
• Diagnosis: clinical not sufficient
• DVT compression ultrasound
+/- doppler
• Pulmonary embolus: CT scan
CT pulmonary angiogram
Venous thrombosis
• Causes: circumstantial
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Surgery
Immobilisation
Oestrogens: OC, HRT
Malignancy
Long haul flights
Venous thrombosis
• Causes: genetic
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Factor V Leiden (5%)
PT20210A (3%)
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Venous thrombosis
• Treatment
• Initial
Low molecular weight heparin, s/c od
weight adjusted dose
• Then
oral warfarin for 3-6 months
Venous thrombosis
• Prevention
• Thromboprophylaxsis
od, s/c, LMWH
TED stockings
early mobilisation and good hydration
Heparin
• Glycoaminoglycan
• Binds to antithrombin and increases its
activity
• Indirect thrombin inhibitor
• Monitor with APTT, aim ratio 1.8-2.8
• Given by continuous infusion
Low molecular weight heparin
• Smaller molecule, less variation in dose and
renally excreted
• Once daily, weight-adjusted dose given
subcutaneously
• Used for treatment and prophylaxsis
Aspirin
• Inhibits cyclo-oxygenase irreversibly
• Act for lifetime of platelet, 7-10 days
• Inhibits thromboxane formation and hence
platelet aggregation
• Used in arterial thrombosis, 75-300 mg od
• Clopidogrel similar, but inhibits ADP
induced platelet aggregation
Warfarin
• Orally active
• Prevents synthesis of active factors II, VII,
IX and X
• Antagonist of vitamin K
• Long half life (36 hours)
• Prolongs the prothrombin time
Warfarin
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Difficult to use,
Individual variation in dose
Need to monitor
Measure INR (international normalised
ratio, derived from prothrombin time)
• Usual target range 2-3,
• Higher range 3-4.5
Direct Oral Anticoagulants
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Oral anti-IIa and anti-Xa inhibitors
Dabigatran, Rivaroxaban, Apixaban
For DVT/ PE and AF
Equivalent to warfarin INR 2-3, but od/bd,
no monitoring
• Cant assay easily or reverse!
3. Transfusion
Red blood cells
• Provide intravascular volume and O2
carrying capacity.
• Transfusion of red cells can be life-saving in
situations of acute intravascular volume
loss, e.g. trauma, surgery
Red blood cells
• Although red cells have a limited life-span,
transfusion to another individual is a form
of tissue transplantation, with similarities to
kidney, heart and bone marrow
transplantation
• Compatibility between donor and recipient
is vital or rejection will occur
Red Cells
• Carry on the surface of their membrane
many different proteins which differ
between individuals
• These are the red cell antigens
• Inherited
• Over 400 different systems of red cell
antigens
• Only 2 very important: ABO and Rhesus
ABO blood group system
• 4 blood groups: A, B, AB and O
• O is recessive, so O = 0,0
• A= AA or AO, B=BB or BO, AB= AB
O= 45%, A= 40%,B=12%, AB= 3%
ABO blood group system
• ABO unusual antigens: carbohydrate, not
protein
• Naturally occuring antibodies from age 6
months
• IgM antibodies in plasma, don’t cross
placenta
• IgM antibodies fix complement to C9, so
transfusion reactions very severe
Rhesus blood group system
• Complex series of C,D and E antigens
• D/d by far most important
• D is a null gene, no protein product, so no
anti-d possible
• D is dominant, so D = DD or Dd
• 15% population dd = d = d negative
Rhesus blood group system
• Women who are rhesus negative (dd) have
babies that carry paternal antigens, such as
D.
• If mother exposed to D red cells will make
IgG anti-D
• Anti-D crosses placenta and haemolyses
babies red cells: can result in in-utero death
and need for in-utero blood transfusion
Other blood groups
• Many in number
• Infrequent problem
• Only likely to have been sensitised if had
previous blood transfusion (occasionally by
pregnancy)
• Can cause major problems with finding
compatible blood
Group and Screen
• Determine ABO group: cells and serum
• Determine Rh D status, using two different
reagents
• Screen serum for presence of preformed
antibodies to any blood group
Cross match
• Specifically determine compatibility between
donor red cells and recipients serum
• Very important if known antibodies or multiple
previous transfusions
• If group and screen neg X 2 may be unnecessary,
use electronic cross-match
Indications for transfusion
• Hypovolaemia due to loss blood
• Severe anaemia with symptoms due to
inadequate oxygenation of tissues
• Anaemia that cannot be corrected by bone
marrow function
Indications for transfusion
• Not indicated for iron deficiency or B12/
folate deficiency.
• Not indicated for minor blood loss,
especially if fit and healthy
(transfusion trigger = 8 g/dl)
• Not indicated for asymptomatic anaemia
Hazards of transfusion
• Blood is tissue from another individual
• Transfusion is potentially fatal, although
used properly can, and does save lives
Early hazards
• ABO incompatibility reaction – can be
rapidly fatal
• Fluid overload, pulmonary oedema
• Febrile reactions, urticarial reactions,
occasionally life threatening respiratory
failure
• Bacterial and malerial infection
Late hazards
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Rh D and other antibody sensitisation
Delayed transfusion reaction
Viral infection: Hepatitis B, C, HIV
? Prion infection: nvCJD
Iron overload: cardiac, hepatic and
endocrine damage
Alternatives to transfusion
• Treat anaemia pre-op
• Use transfusion trigger
• Stop anti-platelet and anti-coagulant drugs
• Consider intra-operative cell salvage and reinfusion
Other components
• Blood is not only red cells
• Also platelets and plasma
• Plasma can be used as it is, or fractionated
to produce concentrates of specific
components, e.g. factor VIII or IX
• White cells only rarely used, as antibiotics
so potent!
Fresh frozen plasma
• Plasma frozen within 6 hours of collection
• Contains all the coagulation proteins and
inhibitors
• Used if massive transfusion and dilutional
coagulopathy, in liver disease and DIC
Platelets
• Correct bleeding due to thrombocytopenia
• Work for lack of production or perippheral
consumption
• Not useful if deficiency is due to immune
anti-platelet antibody
Further reading
• Oxford handbook of clinical medicine
Haematology section
• Essential haematology
Hoffbrand, Petitt and Moss, Blackwell