Coagulation Flashcards
What are the major stages of Haemostasis?
- Damage to Blood Vessel Wall
- Platelet Adhesion to blood vessel wall
- Platelet Activation
- Platelet Plug Formation
- Coagulation Cascade
What is the First Step of the Initiation Phase of the Coagulation Cascade?
What does this step activate?
Activation of Factor VII in the presence of tissue factor.
Contributes to the activation of Factors IX and X
Where does vWF act on the Coagulation Cascade?
Factor VIIIa
Where does Antithrombin act on the Coagulation Cascade?
Factors IXa and Xa and Thrombin (IIa)
Where does Activated Protein C act on the Coagulation Cascade?
What is its mechanism of action?
Va and VIIIa
Inhibits amplification phase
Proteolyses peptide binds in FVa and FVIIIa
deactivates them
Where is Calcium required in the Coagulation Cascade?
Activation of Factor X and II (prothrombin to thrombin)
What does the Thrombin Burst cause?
Positive Feedback
Amplification phase
Activates more Platelets
Activates Factors XI, VIII and V
What factor causes a loose mesh to become a stable clot?
Factor XIIIa
How to Platelets stick to Exposed Collagen?
Glycoprotein Ia
How to vWF and Fibrinogen promote platelet aggregation?
Glycoprotein IIb and IIIa
What are the 3 aims of clot regulation?
- prevent clot formation in normal vessels
- restrict clot to damaged area
- remove clot as tissue repair is completed
What is the role of the Liver in clotting?
Synthesises clotting factors by synthesising bile salts
Bile salts released into the GI tract in bile
Allows absorption of vitamin K (with pancreatic juices)
Post-translational modification produces clotting factors in blood
How is a clot broken down?
Plasminogen in incorporated into a clot
This is activated into plasmin
Plasmin causes the breakdown of fibrin into fibrin degradation products (FDPS)
FDPs are soluble forms of fibrin
What activates plasminogen?
tPA - tissue plasminogen activator
urokinase/streptokinase - fibrinolytic drugs
What activates fibrinogen?
Thrombin
What is the role of the endothelium in preventing clot formation and propagation?
Separates tissue factor and circulating FVII
Cover vWF - prevent platelet adhesion
Collagen not exposed
Glycocalyx - prevents platelet adhesion
Prostacyclin and Nitric Oxide - prevent platelet adhesion and aggregation
CD39 - metabolises ADP released by activated platelets
tPA - involved in clot breakdown
Thrombomodulin - activates protein C, absorbs excess thrombin
Heparin sulfate - cofactor for antithrombin
What is Purpura and what are the different types?
Collective term for bleeding into the skin or mucous membranes
Petechia - small haemorrhages up to pin head size
Ecchymoses - larger haemorrhages
What is thrombocytopenia?
How does it present?
Low blood platelet count
Petechiae in skin and other tissues
What are the indications for Anticoagulant Therapy? (3)
Prophylaxis
Post-Thromboembolic event
During therapeutic procedures
How do anticoagulant drugs work, generally?
What are the different types of anticoagulant drugs?
Prevent or reduce coagulation of blood
Prolong clotting time
Do not stop the formation of a platelet plug
Act on the clotting cascade to prevent fibrin production
Heparin
Warfarin
DOACs
What are the two types of heparin?
Unfractioned heparin
Low molecular weight heparin
What is the mechanism of action of Heparin?
Increases effectiveness of antithrombin-III
Inactivates thrombin and Factors VIII, IX, X, XI, XII
How is unfractioned Heparin administered?
Subcutaneously or Intravenously
What is used to monitor unfractioned heparin?
APTT activated partial thromboplastin time
What is the problem with unfractioned heparin?
absorbed by endothelial cells
unpredictable half life
normally half an hour but can increase up to 2-3 hours when the endothelium becomes saturated and the renal excretion is relied upon
What are some drug options for LMWH?
Clexane, Dolteparin, Nadroparin
What are the benefits of LMWH over unfractioned heparin?
more predictable, binds with low affinity to endothelium
longer duration of action
greater effect on factor X than thrombin so reduced risk of bleeding
only needs to be monitored during pregnancy and renal failure
How is LMWH monitored?
anti-Xa assay
What anticoagulant is first line for DVT/PE and for prophylaxis after surgery?
Low Molecular Weight Heparin
How is LMWH administered?
Subcutaneously
What are the side effects of heparin?
Haemorrhage - exacerbated by alcohol
Osteoporosis - only unfractioned heparin - if used for a few weeks
Thrombocytopaenia - can occur after 7-10 days of therapy - heparin induced antiplatelet antibodies
Hyperkalaemia - due to inhibition of aldosterone secretion
Hypersensitivity
What will prevent the action and reverse the effect of unfractioned heparin?
Protamine Sulphate
In simple terms, What is Warfarin?
Vitamin K antagonist
Which clotting factors are dependent on vitamin K?
Factors II, VII, IX and X
Proteins C and S
What is the specific antidote to warfarin and how should it be administered?
Vitamin K
Orally or intravenously
What is the mechanism of action Warfarin?
Binds to vitamin K reductase enzyme on liver cells
Decreases production of reduced form of vitK
Suppresses production of clotting factors that contain the Gla proteins (Factors II, VII, IX, X; protein C and protein S)
Decreased prothrombin levels and amount of thrombin produced
How is Warfarin Administered?
Orally
What is the effect of LMWH on prothrombin time?
normal
What is the effect of unfractioned heparin on prothrombin time?
mildly prolonged
What is the effect of warfarin on prothrombin time?
prolonged - PT aka INR
What is the effect of LMWH on APTT? (activated partial thromboplastin time)
mildly prolonged, not used for monitoring
What is the effect of unfractioned heparin on APTT?(activated partial thromboplastin time)
prolonged - used for monitoring
What is the effect of warfarin on APTT?(activated partial thromboplastin time)
prolonged
What is the effect of LMWH on thrombin time?
mildly prolonged at therapeutic level
What is the effect of unfractioned heparin on thrombin time?
prolonged
What is the effect of Warfarin on thrombin time?
normal
what is prothrombin time?
blood test
used to see how long it takes for blood to clot
INR
What are the normal values for thrombin time?
12-14 seconds
In simple terms, what are DOACs?
Factor Xa inhibitors
What is the mechanism of action of DOACs?
inhibit prothrombinase complex-bound and clot-asscoaited factor Xa
resulting in reduced thrombin burst
Do not inhibit platelet aggregation but decrease clot formation induced by thrombin
What are some examples of DOACs?
Rivaroxaban, Apixaban, Edoxaban, Betrixaban
When are fibrinolytic/thrombolytic drugs used?
Myocardial Infarction
Cerebrovascular Accident
Venous Thromboembolism
Pulmonary Embolism
What do fibrinolytic/thrombolytic drugs do and how?
Restore blood flow to an area that has been occluded
Dissolve clots by activating plasminogen into plasmin
What are some examples of fibrinolytic/thrombolytic drugs?
Streptokinase
Urokinase
Tissue Plasminogen Activator
What is the mechanism of action of streptokinase?
Complexes with and activates plasminogen
What is the mechanism of acton of urokinase?
Direct acting plasminogen activator
What is the mechanism of action of tPA?
Activates plasminogen
What do antiplatelet drugs do?
decrease platelet aggregation and prevent thrombus formation
what are some examples of anti platelet drugs?
Aspirin and Clopidogrel
What is Clopidogrel?
When is it used?
Antiplatelet
Prodrug - activated by CYP450
Used in atherosclerotic disease to reduce morbid events
What is Desmopressin?
When is it used?
Stimulates release of vWF from endothelial cells
More form and complex with factor VIII
ADH analogue
Haemophilia A and Von Willebrand Disease
