Coagulation Lecture 2 - Approach to Clinical Coagulation Studies

Question 1

Two Major Reasons for Clinical Investigations

Answer 1

1. Investigation of unexplained excess bleeding

2. Monitoring of altered haemostatic function

Question 2

Patient History Categories to Consider

Answer 2

Age of onset
Family incidence 
Duration and severity of bleed
Previous response to trauma
Type of bleed

Question 3

Clinical Disorders

Answer 3

Primary haemostasis
- platelet disorders (quantitative or qualitative)
- vWf disease
- vessel disorders
Secondary haemostasis
- decreased concentration of coagulation factors
- altered function of coagulation factors
- interfering substances (inhibitors)

Question 4

vWf Disease

Answer 4

Characterised by variable clinical inheritance
- many expressions are mild bleeding disorders
Patients will demonstrate characteristically mucocutaneous bleeding
Many patients diagnosed as a result of an investigation for easy bruising or following bleeding after a dental extraction
vWD may be caused by:
- decreased concentration of vWf
- altered function of vWf
Several types and subtypes defined by:
- vWf concentration
- multimeric analysis
- inheritance

Question 5

vWD Laboratory Characteristics

Answer 5

Abnormal PFA-100
Abnormal vWf concentration
Abnormal mutlimeric analysis
Abnormal FVIII:C/aPTT
Normal platelet concentration

Question 6

Disorders of Secondary Haemostasis

Answer 6

Inherited coagulopathies (factor deficiencies)
Acquired coagulopathies

Question 7

Inherited Coagulopathies

Answer 7

Need specific factor assays to assess
The haemophilias:
- FVIII deficiency (haemophilia A)
- FIX deficiency (haemophilia B)
Other 'rare' factor deficiencies:
- FI
- FII
- FV
- FVII
- FX
- FXIII
- (FXII, PK, HMWK)

Question 8

Haemophilias

Answer 8

Intrinsic pathway factor deficiencies
Characteristic screening results => prolonged aPTT
Specific factor levels needed to confirm type of haemophilia
Molecular characterisation of gene lesion
- inversions, deletion, point mutations

Question 9

Haemophilia - Clinical Manifestations

Answer 9

Dependent on factor levels
Broadly classified as mild, moderate and severe
E.g. For haemophilia A:
- severe haemophilia (less than 1% FVIII)
- moderate haemophilia (1-5% FVIII)
- mild haemophilia (6-30% FVIII)

Question 10

Acquired Factor Deficiences

Answer 10

Liver disease
- site of production of factors
Vitamin K deficiency
- need to produce functional factors (II, VII, IX, X)
Inhibitors
- antibodies to a particular factor 
Disseminated intravascular coagulation
- consumption of available factors

Question 11

Anticoagulant Therapy

Answer 11

The aim is to reduce the ‘coagulability’ of circulating blood to decrease thrombotic and/or embolic risk/episodes
Laboratory monitoring is used to monitor effectiveness and guard against increased risk of haemorrhage
Anticoagulant therapy:
- doesn’t remove (lyse) thrombi
- prevents reoccurance of thrombi
- prevents further growth of thrombi

Question 12

Types of Anticoagulants

Answer 12

Coumarin type drugs
- e.g. warfarin
Heparins
- e.g. unfractionated heparin (UFH) and low molecular weight heparin (LMWH)
Other anticoagulants
- e.g. aspirin, hirudin, DOACs
Anticoagulants:
- administered I/V, S/C or orally
- maintaining haemostatic balance requires laboratory monitoring

Question 13

Warfarin

Answer 13

Coumarin derived drug
Inhibits vitamin K dependent carboxylation of:
- coagulation factors II, VII, IX and X
- natural anticoagulants protein C and protein S
Liver production of proteins is normal
Post-translational modification does not occur
γ-carboxyl-glutamic acid deficient factors are produced
Proteins are inactive - impaired coagulation reactions
Reasonably safe although associated with risk of bleeding ay higher dosages with increased age

Question 14

Warfarin - Half Life of Clotting Factors

Answer 14

FVII - 5-6 hours
FIX - 20-30 hours
FX - 45-72 hours
FII - 60-72 hours

Question 15

Heparins

Answer 15

Heavily sulphated acid mucopolysaccharides
Indirect thrombin inhibitors
Unfractionated (UFH) = 15-30 saccharide units
Low molecular weight (LMWH) = < 17 saccharide units
Functions:
- interfere (block) serine proteases (FIIa, FXa) via antithrombin
- potentiates the action of tissue factor pathway inhibitor
- decrease platelet adhesion

Question 16

Heparin Administration

Answer 16

Its done:
- intravenously (I/V)
- subcutaneously (S/C)
- continuous infusion (UFH)
Effect is immediated
Short half life
Heparin and OACT started at the same time
Heparine withdrawn after ~ 3 days
Effective for treatment of DVT and arterial disease

Question 17

Complications of Heparin Therapy

Answer 17

Heparin induced thrombocytopenia:
Antibody mediated
Type 1
- mild
Type 2
- more serious
- ~ 5% of patients receiving UFH
- 5-12 days after the onset of therapy
- usually < 50 x 10^9/L
- arterial/venous platelet thrombi

Question 18

Laboratory Monitoring (UFH)

Answer 18

Variable degree of anticoagulation
Requires close monitoring
For continuous I/V infusion
Monitor every 6 hours and after dose change
Determine ratio from patient control and control aPTT
Compare to therapeutic range: 1.5-2.5

Question 19

LMW Heparins

Answer 19

< 17 saccaride units
Lower MW than UFH
Greater effect on on FXa than on thrombin
Doesn't affect clot based laboratory tests for monitoring heparin i.e. aPTT
Monitoring by chromogenic assay 
- e.g. anti-FXa activity 
Examples:
- Dalteparin
- Enoxaparin
- Tinzaparin

Question 20

Advantages of LMW Heparins

Answer 20

Can overcome limitations of UFH
Has better absorption from S/C site than UFH
More bioavailable
- bind less to plasma proteins and cell surfaces
Has reduced affinity for PF4
- lower HIT frequency
At least as effect or safer than UFH