Haemostasis Flashcards
What two factors keep haemostasis at a state of equilibrium
Fibrinolytic factors and coagulation factors
What is coagulation
The simulation of blood clotting
What is thrombosis
Blood clotting - this limits the extent of the response to the area of injury
What is fibrinolysis
Breakdown of a clot as a part of healing
What are the three processes of haemostasis
1) contraction of blood vessels ( vasoconstriction)
2) formation of an unstable platelet drug at the site of the vessel wall damage ( primary haemostasis ) - includes platelet adhesion and
platelet aggregation
3) formation of a stable fibrin clot ( secondary coagulation )
4) dissolution of clot and vessel repair
Why is it important to understand the haemostatic disorders?
Diagnose and treat bleeding disorders, identify risk factors for thrombosis, treat thrombotic disorders, monitor the drugs that are used to treat bleeding and thrombotic disorders and control bleeding in individuals who do not have any underlying bleeding disorders
What are megakarocytes
A large bone marrow which is responsible for the production of platelets . Platelets are formed by the fragmentation of megakaryocyte cytoplasm
What do platelets do after there has been an injury to a vessel wall
Platelets stick to the damaged endothelium either directly to collagen via GP1a receptor or indirectly via the Von Willebrand factor which binds to the platelet GP1b receptor. This activates platelets
What happens to the shape of the platelet once it becomes activated
Changes from a disc to a more rounded form with spicules to encourage platelet-platelet interaction
What is in the storage granules of platelets
2 types of ultrastructurally identifiable granules : alpha and dense granules. Platelet membrane forms a surface connectedcannalicukar system through which ADP, fibrinogen and Von Willebrand Factor is released
What is a prostaglandin
Prostaglandins are groups of lipids made at sites of tissue damage or infection that control processes of blood flow and blood clots
What is thromboxane A2
A prostaglandin that is produced from arachidonic acid that is derived from the cell membrane. Thromboxane A2 is involved in platelet aggregation and is also a vasoconstrictor that is especially imp in tissue injury and inflammation
How does the granular release of ADP and generation of thromboxane A2 stimulate positive feedback ?
Binding to P2Y12 and thromboxane A12 receptor
To which receptors does fibrinogen bind
GPIIa/IIIa . Platelet activation causes a structural change to these receptors allowing fibrinogen to bind and then further activating and linking platelets together to form a platelet plug.
What prevents inappropriate platelet aggregation
Active flow of blood. Prostacyclin - it is a powerful vasodilator and suppresses platelet aggregation
What are the two most common anti platelet drugs
Aspirin and clopidogrel
How does aspirin work
Aspirin ( a selective anti inflammatory drug ) inhibits the production of thromboxane A2 by irreversible blocking the action of cyclo-oxygenase ( COX) resulting in a reduction in platelet aggregation as prostaglandin can no longer be formed . Effects of aspirin last for around 7 days , until most of the platelets have been replaced by new platelets
Disadvantages of high aspirin dose
Aspirin also interferes with the synthesis of endothelial cell prostacyclin and therefore when it is used as an anti thrombotic agent , it is used in lower doses. But endothelial cells can synthesis more COX, whereas platelets cannot as they have no nucleus to synthesis new RNA.
How does clopidogrel work
Irreversibly blocks ADp receptor( P2Y12) on platelet cell membrane which stimulates platelet aggregation . Effects last for 7 days
What is VWF
Glycoprotein that is stimulated by endothelial cells and megakaryocytes and circulates in plasma. Mediates adhesion of platelets to sited of injury and promotes platelet-platelet aggregation, also specific carrier for factor VIII.
Formation of a stable fibrin clot ( secondary haemostasis)
1) primary platelet plug is insufficient for small vessel injury
2) will fall apart in large vessels
3) fibrin formation stabilises platelet plug
4) thrombin cleaves fibrinogen to generate fibrin clot that stabilises platelet plug at site of injury
Where are the clotting factors synthesised
Liver with exception of VWF and factor VIII
Which clotting factors are made by endothelial cells
Factor VIII and VWF
Vitamin K helps in the function of which clotting factors
Factors II( prothrombin ), VII, IX and X . Vitamin K carboxylate glutamic acid residues which is essential for the function of these clotting factors
What is each step in blood coagulation characterised by
Conversion of inactive zymogen ( proenzyme) into an active clotting factor by one or more peptide bonds and exposure or active enzyme site
Which clotting factors are cofactors
Factors 5 and 8
Which metal ion plays an imp role in the binding of activated clotting factors to phospholipid surfaces of platelets
Calcium
What occurs in secondary haemostasis up until the initiation phase
1) Blood escaping from an area of damage is exposed to tissue factor. TF is not normally exposed to blood , blood only encounters TF at sites of vascular injury
2) TF binds to factor VII in plasma and forms activates complex and coagulation is initiated
3) factor VII converts: factor X to Xa and IX to IXa
What happens during initiation of coagulation
Factor Xa converts factor II ( prothrombin) to IIa( thrombin)
What happens during amplification of coagulation
Thrombin activates cofactors ( V to Va and VIII to VIIIa)
What happens during propagation of coagulation
Rapid burst of thrombin generation which cleaves circulation fibrinogen ( soluble) to form insoluble clot
What are natural anticoagulant pathways
Inhibitory mechanisms that prevent blood from clotting completely whenever clotting is initiated by vessel injury
Describe the inhibitory pathway between thrombin and thrombomodulin
Thrombin binds to thrombomodulin on the endothelial cell surface leading to the activation of protein C to activated protein C (APC). APC inactivated factors Va and VIII a ( cofactors) in the presence of co factor protein S
Describe the anticoagulation pathway between thrombin and factor Xa
Thrombin and factor Xa and inactivated by circulating inhibitor antithrombin. The action of antithrombin is markedly potentiated by heparin : this occurs physiologically by binding of antithrombin to endothelial cell-associated heparins
What are the three main anticoagulant drugs
Heparin, warfarin and direct oral anticoagulants (DOAFs). These drugs are used in the prevention and treatment of thrombosis
How does heparin work
Indirectly by potentiatung action of antithrombin leading to the inactivation of factors Xa and IIa ( thrombin). Administered intravenously or subcutaneously ( fat layer in lower belly)
How does Warfarin work
It is a vitamin K antagonist so interferes with protein carboxylation. Reduces synthesis of functional factors produced by liver ( all apart from factor VIII). Oral tablet and needs to be monitored by regular blood tests. Takes several days to take effect as reduces synthesis of coagulation factors rather than inhibiting existing coagulation factors.
How do DOAC’s work
Inhibit either thrombin or factor Xa. Orally and do not unusually require monitoring
What is the principle fibrinolytic enzyme
Plasmin and it circulates in it’s inactive zymogen form plasminogen. Activation of plasminogen is mediated by tissue plasminogen activator ( t-PA) . But t-PA does not activate the plasminogen until these are bothe brougth together by binding to lysine residues on fibrin. The breakdown of fibrin leads to the generation of fibrin-degredation produces.
Is plasmin specific to fibrin
No, it can also break down other protein components of plasma, including fibrinogen and the clotting factors Va and VIIIa. Plasmin is inhibited by antiplasmin which circulates in blood
What is thrombolytic therapy
Thrombolytic agents such as recombinant t-PA works by generating plasmin to lyse clots and are administered intravenously . High risk of bleeding associated with use. Needs to be administered quickly to people with pulmonary emboli etc.
How do anti fibrinolytic drugs work
Tranexamic acid is a synthetic derivative of amino acid lysine with binds to plasminogen . Competitive inhibition so plasminogen cannot bind to lysine residues of fibrin and fibrinolysis cannot occur. Used to treat bleeding in trauma and surgical patients as well as in inherited bleeding disorders
What is intrinsic coagulation
Refers to a system in which all components are in the plasma ( factors XII, XI, IX , X and cofactors VIII and V)
What is the extrinsic system
Comprises of TF and factors VII, X and cofactor V
What is a coagulation screen
Always includes Prothrombin time and an activated partial thromboplastin time. May include thrombin time and an assay of fibrinogen
What is done to the plasma before coagulation screens are carried out
Platelet poor plasma is used and therefore the plasma from the blood is anticoagulated with sodium citrate and has been centrifuged to remove platelets
What does the prothrombin time test
Assessed extrinsic pathway. A source of TF , phospholipid and calcium is added to reverse effect of citrate coagulant and time taken to clot is measured ( 12-14 sec). Dependent on factors VII, X, V and II .
What does prothrombin time test do
Measures time taken for blood to clot. Measures clotting ability of factors 1,2,5,7,10. Thrombin is added to plasma for test . Results of this test are normal for people with haemophilia A ( factor 8 deficiency) and B( factor 9 deficiency).
What is activated partial thromboplastin time
Assesses intrinsic pathway ( factors 12,11,9,8,10,5 and 2). Contact activator, together with phospholipid is added to citrate sample followed by calcium.
What changes to haemostasis causes bleeding?
1) reduction in platelet number or function ( primary haemostasis - platelet plug)
2) reduction in coagulation factor ( secondary haemostasis - fibrin clot)
3) increased fibrinolysis
What may cause a reduction in platelet number ( thrombocytopenia)
Failure of platelet production : drugs, viruses, bone marrow infiltration life megobkastic anemia, hereditary thrombocytopenia , increase in splenic pooling
What may cause a reduction in platelet function
Antiplatelet drugs ( aspirin), inherited causes
What may cause reduction in coagulation factors
Congenital: VWD, haemophilia A ( factor 8) , haemophilia b ( factor 9)
Aquifer: liver disease ( affects factors 2,7,9,10), anticoagulant drugs, disseminated intravascular coagulation ( DIC),
What may cause increase in fibrinolysis
DIC, administration officials thrombolytic therapy ( tPA)
What is Virchows triad( the three factors towards thrombosis)
Blood ( dominant in venous thrombosis ), vessel wall ( dominant in arterial thrombosis), blood flow
Changes in blood that increases risk of venous thrombosis
Reduced levels of anticoagulant proteins, reduced fibrinolytic activity, increased levels of clotting factors or platelets
