Haemostasis Flashcards
What balance is required in haemostasis
Fibrinolytic factors, anticoagulant proteins Coagulation factors, platelets
Why is the balance in haemostasis important
Allows the stimulation of blood clotting processes following injury Limit the extent of the response to the area of injury to prevent excessive or generalised blood clotting Start the process of fibrinolysis
What does haemostasis describe
Halting of blood following trauma Contraction of blood vessels Formation of unstable platelet plug Formation of stable fibrin clot
How would you describe platelets
Discoid, non-nucleated, granule-containing cells Plasma membrane contains glycoproteins
How to platelets stick to damaged endothelium
Directly to collagen via the platelet GP1a receptor Indirectly via Von Willebrand Factor which binds to platelet GP1b receptor Activation causes change of disc to rounded form which spicules to encourage interaction
What does adhesion of platelets mean
Release contents of their storage granules: a-granules and dense granules by invaginating their platelet membrane Components of the contents include ADP, fibrinogen and VWF
What does thromboxane A2 do (platelets are stimuated to make this)
Platelet aggregation Vasoconstrictor From arachidonic acid Tissue injury and inflammation
What do ADP and thromboxane A2 do
Positive feedback effects resulting in further platelet recruitment activation and aggression They do this by binding onto P2Y12 and thromboxane A2 receptor
What does platelet activation do in terms of GP2b/3a receptor
Conformational change of receptor Fibrinogen binds to it which further activates the platelets Fibrinogen causes the platelet plug However suppressed by PG12 (prostacyclin) which is released from endothelial cells and is a powerful vasodilator and suppresses platelet activation
What are antiplatelet drugs used for
Prevention and treatment of cardiovascular and cerebrovascular disease
What does aspirin do
Inhibits the production of thromboxane A2 by irreversibly blocking the action of cyclo-oxygenase(COX) COX also inhibits prostacyclin However endothelial cells can synthesise more COX whereas platelets can’t Aspirin last 7 days until the platelets present have been replaced
How does clopidogrel work
It irreversibly blocks the ADP receptor (P2Y12)
What is the Von Willebrand factor
Glycoprotein Synthesised by endothelial cells and megakaryocytes Circulates the plasma as multimers of different sizes It mediates the adhesion of platelets Promotes platelet-platelet aggregation Specific carrier for factor VIII
Why is secondary haemostasis (coagulation) needed
Primary platelet plus is sufficient for small vessel injuries Fibrin formation stabilises the platelet plug
All but two clotting factors are synthesised in the liver
Factor VIII and VWF
What factors are dependent on Vitamin K for carboxylation of glutamix acid residues
Factor 2, Factor VII, UX X
What does the process of blood coagulation entail
Inactive zymogen (proenzyme) into an active clotting factor
Where are many clotting factors believed to work on
Exposed phospholipid surface surface of platelets
What do calcium ions play an important role in
Binding of activated clotting factors
Diagram of platelet activation
What is the trigger to initiate coagulation
Tissue factor
(located at sites where blood is normally not exposed to)
This means that blood only encounters TF at the site of injury
What is the initiation phase of coagulation
Tissue factor binds to factor VIIa which activate IX to IXa and X to Xa
Leads to the activation of prothrombin (factor 2)
Generate a small about of thrombine factor 2a
What is the amplication phase of coagulation
Small amounts of thrombin activates cofactors V and VIII, the zymogen factor XI and platelets
What is the propagation phase in coagulation
Factor 6 converts more factor IX to factor IXa, which in cocert with factor VIIa, amplifies the conversion of factor X to Xa and there is a rapid burst in thrombin generation which cleaves fibrinogen to form fibrin
What are the anticoagulants
Thrombin binds to thrombomodulin on endothelial cells leading to acitvation of protein C to activated protein C. APC inactivates factors Va and VIIIa in prescence of of protein S
Thrombin and factor Xa are inactivated by antithrombin by binding of antithrombin do endothelial cell associated heparins
What is heparin
Mixture of glycosaminylglycan chains
Potentiating the action of antithrombin leading to inactivation of Xa and factor 2a
Inactivation of thrombin requires longer chain of heparin chains which can wrap around antithrombin and thrombin
Intravenously or subcutaneous injection
Warfarin
Vitamin K antagonist (interferes with protein carboxylation)
Reduces synthesis of 2, VII, IX and X by the liver
Oral tablet
Reduce synthesis so takes a few days
What are DOACs
Direct oral anticoagulants
Directly inhibit thrombin or factor Xa
Do not require monitoring
What is the activation of plasmin mediated by
Tissue plasminogen activator (t-PA)
Why doesn’t t-PA activate plasminogen
Need to be brought together by binding to lysine residues
What does the breakdown of fibrin lead to
Generation of fibrin-degradation produces
What other products can plasmin breakdown
It can breakdown fibrin, fibrinogen and clotting factors Va and VIIIa
What type of thrombolytic therapy is there
Recombinant t-PA work by generating plasmin to lyse clots
Administered intravenously
Time beneficial
High risk of bleeding
What are antifibrinolytic drugs
Tranexamic acid is derivative of lysin that binds to plasminogen
It prevents plasminogen binding to the lysine residue of fibrin
Competitive inhibition
Used to treat bleeding in trauma and surgical patients
Diagram of intrinsic and extrinsic pathway
Intrinsic is in the plasma and factor XII, XI, IX, X and co-factors VIII and V
Extrinsic is TF and factor VII, X and co-factor V
What does the prothrombin time do
Measures the integrity of the extrinsic pathway
How is PT measured
Blood collected into bottle containign sodium citrate (stops calcium from clotting)
Spun to produce platelet poor plasma
TF and phosphilipid is added together with calcium to start the reaction
Length of time for mixture to clot is recorded
Normally recombinant thromboplastin is used as the source of both TF and phospholipid
When PT is used to mointor bitamin K antagonist results are express as the international normalised ratio to correct different laboratories results
How does APTT work
Contact activation of factor XII such as silica or kaolin
Phospholipid also added to citrated plasma sample followed by calcium
Time to clot measured
Prolongation of APTT shows there is a reduction in clotting factors
An isolated prolonged APTT seend in haemophilia A (VIII) haemophilia B (IX) and factor XI deficiency might not be because of the intrinsic pathway why?
Can be caused by factor XII deficiency which is not important for clotting in vivo
What might result in bleeding
Reduction in the platelet number of function (primary haemostasis - platelet plug)
Reduction in coagulation factors (secondary haemostasis - fibrin clot)
Increased fibrinolysis
Why we bleed (reduction in platelet number - thrombocytopenia)
Failure of platelet produciong - drugs, viruses, bone marrow infiltration, egaloblastic anaemia, hereditary thrombocytopenia
Shortned platelet survival - immune thrombocytopenia, disseminated intravascular coagulation
Increased splenic pooling
Reduction in platelet function
Antiplatelet drugs
Inherited causes
Reduction in coagulation factors (congenital)
Von Willebran Disease (VWD) disorder
Haemophilia A - (Factor VIII deficiency, X linked)
Haemophilia B (Factor IX deficiency, X linked)
1 % of patients have deficiencies in one of the other clotting factors
Replacing clotting factor main treatment
What are acquired causes of reduced coagulation factors
Liver disease
Anticoagulant drugs
Disseminated intravascular coagulation (DIC)
Uncontrolled activation of coagulation followed by activation of the fibrinolytic system
Results in the expression of TF within the circulation and leads to generation and dissemination of large amounts of thrombin, activation and consumption of platelets (thrombocytopenia) and formation of thrombin in small blood vessels (microcirculation)
Clotting factors and fibrinogen become deleped
High levels of fibrin degradation products
Thrombi may cause shearing of circulating red blood cells
Causes of DIC
Bacterial sepsis
Advanced cancer
Obstetric emergencies
Inreased fibrinolysis
Administration of thrombolytic therapy
Contributing factors to thrombosis
Blood: dominant in venous thrombosis
Vessel wall: dominant in arterial thrombosis
Blood flow: complex, contributes to both arterial and venous thrombosis
Changes in blood that increase the risk of venous thrombosis
Reduced levels of anticoagulant proteins (usually genetic e.g. inherited thromobophilia)
Reduced fibrinolytic activity (pregnancy inhibition of plasminogen activation)
Increased levels of clotting factors or platelets (factor VIII increase during pregnancy, factor V leiden makes factor V more resistant to inactivation by protein C)
Platelets increase in myeloproliferative disorders, bone marrow output is increased
