Disorders Of Blood Coagulation Flashcards
Why is blood clotting a good thing?
- Stops bleeding at the site of injury
- Keeps blood in and pathogens out
What activates clotting?
Endothelium in blood vessels normally maintains an anticoagulant surface- when this is broken, collagen is exposed which activates clotting
Why must clotting remain localised?
Systemic blood clots not wanted
What is involved in primary haemostasis?
- Platelet adhesion, aggregation, activation
What is involved in secondary haemostasis?
Activation of fibrin formation through the clotting cascade
What occurs in the vessels when there is injury?
- Endothelium in blood vessels normally maintains an anticoagulant surface
- Circulating factors e.g fibrinogen precursor of fibrin in the blood in the inactive form.
- Damage to vessel wall triggers primary and secondary haemostasis.
- Injury exposes collagen to come into contact with blood components to activate clotting.
What happens in primary haemostasis?
- If collagen becomes exposed to blood, von willebrand factors bind to it
- Von willebrand factors bind to platelets from blood and activate them
- Activated platelets express functional fibrinogen receptors which are required for aggregation
What happens in secondary haemostasis?
- Tissue factor activates the coagulation cascade to initiate a minor burst of thrombin
- Factor VIIa binds to tissue factor which ultimately leads to conversion of prothrombin to thrombin
- Thrombin activates receptors on platelets and endothelium → amplification of platelet aggregation and release of von willebrand factors
What is the amplification step of secondary haemostasis?
- Thrombin activates two cofactors, Factor VIIIa and factor Va
- This subsequently forms calcium ion-dependent complexes on the surface of platelets with factor IXa (tenase complex) which activates factor Xa
What does the tenase complex do?
Accelerate production of factor Xa
What does the prothrombinase complex do?
Activate thrombin
What is plasminogen?
Plasminogen is a precursor for plasmin
What is plasmin?
- Plasmin is a potent proteolytic enzyme.
- Plasmin breaks down fibrin into fibrin fragments
What is an example of fibrin degredation products?
- D-dimer
- D-dimer is a marker in disorders
What is fibrinolysis?
Fibrinolysis is the same as thrombolysis
What is the process of fibrinolysis?
- Plasminogen → Plasmin by tissue plasminogen activator (tPA)
- Plasmin then degrades the fibrin mesh → fibrin degredation products
Why are natural anticoagulants important?
- Natural anticoagulants are important to keep coagulation in check.
- Too much coagulation is detrimental so its vital to have anticoagulant pathways to prevent too much thrombin formation
What is thrombin responsible for activating?
Thrombin is responsible for activation of:
- von Willebrand factor from endothelial cells
- factors Xa and IXa
- platelets
Where is tissue plasminogen activator found?
Endothelial cells
Where is antithrombin found?
On the surface of endothelial cells by binding to heparan binding sites on the endothelial cell surface, this binding to heparan greatly enhances antithrombin activity
What is heparin and what does it do?
An anti-coagulant drug that is similar in structure to heparan to enhance the activity of antithrombin
What are protein C and S?
Natural anticoagulant plasma proteins
What is protein C activated by?
Thrombin bound to thrombomodulin on endothelial cells
What does protein S do?
Protein S allows for APC to bind to other molecules e.g. platelets etc.
What does APC do?
Degrades cofactors FVa and FVIIIa in the coagulation pathway
What are three blood clotting disorders?
- Haemophilia
- Thrombophilia
- Disseminated intravascular coagulation
What is haemophilia?
Failure to clot leading to haemorrhage
Describe some of the different ways that one can have haemophilia
- Mutations in coagulation factors (haemophilia A or B)
- Platelet disorders (von Willebrand disease)
- Collagen abnormalities (fragile blood vessels and bruising)
What are haemophilia A and B ?
- Mutations in coagulation factors
How common is is haemophilia B and what mutation causes it?
- Mutated clotting factor 9
- 20% of haemophilia cases
How common is is haemophilia A and what mutation causes it?
- Mutated clotting factor 8
- 80% of haemophilia cases
What is von willebrand disease categorised as?
Platelet disorder
What do collagen abnormalities cause?
Fragile blood vessels and bruising
What is thrombophilia?
Excessive clotting leading thrombosis
Describe some different ways that one can have thrombophilia
- Inherited – mutations in coagulation factors
- Acquired – malignancy increases clotting factors
What causes inherited thrombophilia?
Mutations in coagulation factors
What causes acquired thrombophilia?
Malignancies such as cancer may increase clotting factors
What is disseminated intravascular coagulation (DIC)?
Systemic clotting (Whole body clots)
Where does bleeding occur in haemophilia vs vWF disease?
Haemophilia - in the joints like the knees
vWF - (is milder and often just treated by being careful and lifestyle choices) affects the mucus membranes so there may be bleeding around the gums
How does Factor V Leiden Mutation lead to excessive clotting?
Resistance to APC → FVa not activated → increased risk of DVT (deep vein thrombosis)
How does antithrombin deficiency lead to excessive clotting?
- Thrombin, IXa and FXa are not inactivated – clotting increases
- Increases risk of DVT
What are some causes of excessive clotting?
- Factor V leiden mutation
- Antithrombin deficiency
- Protein C deficiency
- Protein S deficiency
What does DVT development depend on?
- Alterations in the blood constituents
- Changes in normal blood flow
- Damage to the endothelial layer
What are the symptoms of DVT?
- Pain and tenderness of veins
- Limb swelling
- Superficial venous distension
- Increased skin temperature
- Skin discolouration
What are the risks with DVT?
- If the clot is above the knee it is significantly more likely to embolise
When does disseminated intravascular coagulation occur and why?
- Occurs in infection and sepsis (body’s response to an infection injures its own tissues and organs)
- So much coagulation that there is depletion of clotting factors and platelets leads to bleeding
What happens in disseminated intravascular coagulation (DIC)?
Depletion of clotting factors and platelets leading to bleeding so there is coagulation and bleeding occurring at the same time
What do anticoagulants do?
Prevent more clotting
What do thrombolytics/ fibrinolytics do?
Reverse clotting
Give some examples of anticoagulants
- Warfarin
- Heparin
- Direct oral anticoagulants (DOACs)
Give examples of thrombolytics/fibrinolytics
Plasminogen activators : TPA, streptokinase
What does VTE stand for?
Venous thrombus embolism
What pre-treatment investigations can you give for VTE?
- Clotting screen
- FBC
- Renal screen
- Liver function tests
What does the clotting screen show?
- Prothrombin time
- Partial thromboplastin time
- Thrombin time
What are the treatments for DVT?
Anticoagulants
What are examples of DOACs?
- Rivaroxaban and apixaban
- Dabigatran
What are some bleeding complications from anticoagulants?
- Anything from nosebleed up to intercranial haemorrhage in severe cases
