CVS Lecture 13/14 - Haemostasis and Thrombosis Flashcards
What are the functions of haemostasis?
Prevention of blood loss from intact vessels and arrest of bleeding from injured vessels
What is haemostasis important for?
Diagnosis of bleeding disorders, treatment of bleeding disorders, ID of risks from thrombotic disease, treatment of thrombotic disease, monitoring of anticoagulant drugs
How is the haemostatic plug formed?
Response to injury -> vessel constriction -> formation of unstable platelet plug -> stabilisation of plug with fibrin -> dissolution of clot and vessel repair
What are the mechanisms for formation of an unstable platelet plug?
Platelet adhesion, platelet aggregation
How does platelet adhesion and aggregation occur?
Endothelial cell damage reveals sub endothelial structures, such as collagen, which binds to von Willebrand factor (senses the damage) and then captures a platelet through Glycoprotein 1b -> PASSIVE. Platelets can also recognise the collagen and bind directly via Glycoprotein 1a -> PASSIVE. THEN, when receptors become engaged they signal and partially activate the platelet which releases ADP and TXA2 from storage granules -> which then causes platelet aggregation via Glycoprotein 2b/3a receptor on platelet which normally is hidden and needs ADP/TXA2 so that it can become active
Where is von Willebrand made?
Endothelial cells
Why are there several mechanisms by which platelets adhesion can occur?
Differing flow conditions in the vasculature
What other ways can platelet activation occur?
Thrombin -> produced by coagulation activation; when thrombin further cleaves a certain receptor which further activates the platelet
Where are platelets from?
Fragments of megakaryoctes -> half life of 10 days
How does an activated platelet differ from a non-activated one?
Activated platelets change shape (round to pseudopodi and round shape), change membrane composition (important for fibrinogen attachment, coagulation occurs on the surface of the platelet), present new/activate proteins on their surface
Where are clotting factors, fibrinolytic factors and inhibitors synthesised?
Liver, endothelial cells and megakaryocytes -> most in liver but some produced in high local concentration in endothelium (vWF) and megakaryocyte (factor V)
What is the blood coagulation cascade?
All proteins as zymogen -> need to be activated. XIIa can be activated by endothelial surface (damage) -> VIIIa is a co-factor decreasing the time taken for X->Xa. Xa can be formed via enxtrinsic (tissue factors trigger factor VIIa to become activated and form Xa) and intrinsic pathway -> Xa converts protrhrombin to thrombin (which activates FVIII to FVIIIa so it can form even more thrombin, and FVa also undergoes this) -> the common pathway occurs on the surface of the cell
What is the tissue factor?
It isn’t normally visible, as it forms a layer under the endothelium, so when there is damage to the vessel it becomes exposed and hence activates the clotting cascade -> TRIGGER for coagulation initiation
What do the activated platelets help to do in the coagulation system?
They localise and accelerate the reactions
How does fibrinolysis occur?
Tissue plasminogen activator (tPA) circulates inactively which when it comes into contact with a fibrin clot where it undergoes a conformational change and converts plasminogen to plasmin which starts to break down the clot, releasing fibrin degradation products
What are used for therapeutical thrombolysis for MI?
tPA and streptokinase
Why does blood not clot completely whenever clotting is initiated by vessel injury?
Coagulation inhibitory mechanisms prevents this
What are the 2 coagulation inhibitory mechanisms?
1) Direct inhibition (antithrombin is inhibitor of thrombin/other clotting proteinases) 2) Indirect inhibition (of thrombin degradation by protein C anticoagulant pathway)
Which are the coagulation proteinases and what does antithrombin do to them?
Inhibits them, forming an irreversible complex -> heparin makes antithrombin work faster. Coagulation proteinases are: Thrombin, Xa, IXa, XIa, XIIa, VIIa
What does heparin do and what is it used for?
It accelerates the action of antithrombin -> used for immediate anti-coagulation in venous thrombosis and pulm embolism
What happens in the protein C pathway?
Thrombin when coagulation is activated, binds to thrombomodulin, which then activates protein C which with Protein S (co-factor) and inactivate Factor Vai and VIIIai, so decrease synthesis of thrombin
What happens when coagulation inhibitory mechanisms fail?
Antithrombin deficiency (inherited), Protein C/S deficiency and Factor V leiden -> all risks for thrombosis
What is factor V Leiden?
Not so easily inactivated by Protein C
How does the balance tip towards bleeding?
Too much activity from fibrinolytic factors and anticoagulant proteins; decreased activity of coagulation factors and platelets
What are the characteristics of abnormal bleeding?
Spontaneous, out of proportion to the trauma/injury, unduly prolonged, restarts after appearing to stop
What is the response to injury to endothelial cell lining?
What are the main components in primary haemostasis and what are common examples of deficiencies or defective versions of these components?
Collagen -> steroid therapy, age, scurvy; von Willebrand factor -> vW diseases (genetic deficiency); Platelets -> aspirin and other drugs, thrombocytopenia
What happens if there is a deficiency/defect of vWF?
Platelets aren’t captured, so there is failure of primary haemostasis
What is the pattern of breathing for a patient with defects of primary haemostasis?
Immediate, easy bruising, nosebleeds (>20min), gum bleeding (prolonged), menorrhagia (anaemia), bleeding after trauma/surgery, petechiae
What are petechiae and what are they typical of?
Red/purple spots under the skin due to bleeding -> typical of thrombocytopenia (deficiency of platelets in blood)
What is the main factor of the coagulation phase?
Thrombin, which rises after a short lag phase in normal people until inhibited
What is the function of the fibrin mesh that the platelets form?
Binds and stabilises platelet plug and other cells
What is bleeding like in coagulation disorders?
Not enough fibrin is made, so in larger vessels the clot isn’t stable
What are some common examples of defects/deficiencies in coagulation factors?
Genetic -> haemophilia (FVIII or FIX deficiency); Liver disease (acquired); drugs (wafarin - inhibits synthesis, other block functions); Dilution (from volume replacement); Consumption (disseminated intravascular coagulation - acquired)
What is disseminated intravascular coagulation?
Generalised activation of coagulation -> tissue factor; associated with sepsis, major tissue damage, inflammation; consumes and depletes coagulation factors and platelets; activation of fibrinolysis depletes fibrinogens
What are the consequences of disseminated intravascular coagulation?
Widespread bleeding, from IV lines, bruising, internal; deposition of fibrin in vessels causes organ failures
What is the pattern of bleeding in secondary haemostasis disorders/defects?
Delayed and prolonged -> deeper in joints and muscles; not from small cuts (as primary haemostasis OK); nosebleeds rare; bleeding after trauma/surgery
What are some symptoms in bleeding disorders?
Easy bruising (ecchymosis) - all bleeding disorders. Haemarthrosis - haemophilia hallmark
What are 2 types of defects of excess fibrinolysis and some common examples?
Excess fibrinolytic (plasmin, tPA) -> therapeutic administration, some tumours. Deficient antifibrinolytic (antiplasmin) -> antiplasmin deficiency (genetic)
What are some disorders of anticoagulant excess?
Usually due to therapeutic administration -> heparin, thrombin and Xa inhibitors
What is thrombosis?
Intravascular/inappropriate coagulation, coagulation inside a blood vessel, not preceded by bleeding -> may be venous/arterial
What are the effects of thrombosis?
Obstructed flow of blood -> artery [MI, stroke, limb ischemia], vein [pain and swelling]. Embolism -> venous [to lungs =PE], arterial [from heart, may cause stroke/limb ischemia]
What is DVT?
Venous return of blood is obstructed -> painful, swollen leg -> can cause pulmonary embolism which causes sudden death sometimes
What is the prevalence of venous thrombo-embolism?
Overall 1 in 1000-10000; increases with age -> PE causes 10% of hospital deaths; 5% case mortality
Why do some people get thrombosis?
Genetic constitution, effect of age and previous events/illnesses/medication, acute stimuli
Describe this graph
Different people start with different genetic risks, which then accumulate risks from environment and reach the thrombotic threshold
What is Virchow’s triad?
3 contributary factors to thrombosis: Blood -> dom in venous thrombosis. Vessel wall -> dom in arterial thrombosis. Flow -> complex, contributing to both
Which blood related factors increase the risk of thrombosis?
Deficiency of anticoagulatory proteins -> antithrombin, protein C/S. Increased coagulant proteins/activity -> factor VIII, II, V Leiden; thrombocytosis.
What vessel wall related factors increase the risk of thrombosis?
Many proteins active in coagulation on surface of endothelial cells -> thrombomodulin, TF/pathway inhibitor; and the expression of these are altered in inflammation -> malignancy, infection, immune disorders
What flow related factors increase the risk of thrombosis?
Reduced flow (stasis) increases the risk of venous thrombosis -> caused by surgery, fracture, long haul flight, bed rest
How do you identify thrombophilia?
Thrombosis at young age, idiopathic thrombosis, multiple thromboses, thrombosis whilst anti-coagulated; lab can find identifiable cause of increased risk
What are some other risks for thrombosis?
Pregnancy, malignancy, surgery, inflammatory response
What treatment can be used to lyse clot?
tPA -> high risk of bleeding
What treatment can be used to limit recurrence/extension/emboli?
Increase anticoagulant activity (heparin); lower procoagulant factors (warfarin); inhibit procoagulant factors - direct inhibitors (rivaroxaban/apixaban (Xa), dabigatran (IIa)
What is the treatment and prevention of thrombosis?
