Lecture 32 Flashcards
(25 cards)
Haemostasis
Arrest of blood loss from damages vessel therefore, essential for survival. Involves platelet adhesion to damaged vessel wall, platelet activation (express surface proteins and secrete ADP and TXA2 which cause platelet aggregation), further aggregation with active platelets (involves GPIIb/IIIa receptor) and blood clot formation via fibrin.
Mechanisms in haemostasis
Platelets adhere, aggregate and activate, secreting ADP, thromboxane A2 and platelet activating factor occur increasing platelet aggregation. Simultaneously, exposure of acidic phospholipids occur which activates blood coagulation pathway. Activation of one factor catalyses activation of larger amounts of next factor and so on. Thrombin converts soluble fibrinogen to insoluble strands of fibrin achieves by cleavage reactions. Fragments polymerise to form fibrin which combine to form fibrin threads that form clot.
Platelet reactions
P2Y1 and P2Y12 receptors are expressed on platelets and bind ADP (GPCR). TPalphaR also expressed on platelets and bind thromboxane A2 also GPCR and involved in activation. PAR-4 GPCR bind thrombin and work in conjunction with other receptors to enhance activation and aggregation. GPIIb/IIIa bind fibrinogen which leads to aggregation. Thromboxane A2 and ADP produced by proteins increased expression of GIIb/IIIa = increase aggregation.
Blood coagulation
Extrinsic arises from in vivo events involving tissue factors and factor 7A. Intrinsic pathway which begins when factor 12 adheres to negatively charged surfaces and converges with extrinsic pathway at stage of factor 10 activation. Enzyme cascade controlled by inhibitors incl. antithrombin III neutralises factor 10A and 2A activation. Vitamin K is needed for factor 7,10 and 2 formation.
Incorrect haemostasis
In wrong place AKA Virchow’s triad. Arises due to injury to vessel wall/endothelial dysfunction e.g atherosclerotic plaque rupture, altered blood flow or abnormal blood coagulability.
Role of vascular endothelium
Can change focally from a non-thrombogenic to thrombogenic structure in response to different demands. Usually non-thrombogenic surface by virtue of membrane heparine sulfate which is a cofactpr for antithrombin III. Following clotting, fibrinolysis occurs which dissolves the clot by removing intravascular fibrin and restoring normal blood flow therefore fibrin clot solubilisation is vital for healing. Fibrinolysis activated by thrombin by stimulating tissue plasminogen activator (t-PA) release by endothelial cells and urokinase (u-PA) which mediates plasminogen to plasmin. Plasminogen activator inhibitor I (PAL-1) is main pathway antagonists and is released in response to antgiotensin-4 who’s receptors are present on intracellular endothelial cells, linking renin-angiotensin-aldosterone system to thrombosis. Plasmin intern interacts with fibrin and fibrinogen leading to its degradation by plasmin and other factors.
Incorrect haemostasis
In wrong place AKA Virchow’s triad. Arises due to injury to vessel wall/endothelial dysfunction e.g atherosclerotic plaque rupture, altered blood flow or abnormal blood coagulability
Arterial thrombi
Composed of white thrombus (platelets in fibrin mesh), associated with atherosclerosis and can interrupt blood flow causing ischaemia or death of tissue downstream.
Treatment of infarction
In MI, sympathetic NS activated, increased O2 demands of myocardium. Drugs for MI aim to increase cardiac function by maintaining oxygenation and decrease cardiac work and treating pain while preventing further thrombosis
Venous thrombi
Composed of red thrombus (small white head and red jelly tail). Embolus can lodge in pulmonary artery (pulmonary embolism) or leg (deep vein thrombosis.
Warfarin
Vit. K antagonist by competing with it for reductase enzyme, Orally taken, takes days to have effects and is associated with many drug interactions. Narrow therapeutic window therefore, use needs to be monitored to ensure that its [plasma] is within the correct range without leading to toxic effects. Crosses placenta therefore not given in early/late pregnancy.
Heparin and low molecular weight heparins
LMWs longer active than heparins and is usually preferred. Inhibits coagulation by activating antithrombin III (inhibits factor 10A) therefore, decrease blood clotting. Given through injection. LMWs more predictable than heparin and dosing is less frequent.
DOACs
Direct oral anticoagulants. Inhibitors of factor 10A e.g rivaroxaban and apixaban. Oral administration.
Hirudins
Direct thrombin inhibitors. PPs from anticoagulant present in leech saliva e.g lepuridin and bivalirudin. IV bolus administration.
Anticoagulants
Directly blocking thrombin and F10A prevents coagulation and clot formation. Hirudins and DOACs have higher offset/onset of action that warfarin decreases need of routine blood monitoring.
Aspirin
Aspirin irreversibly inhibits cyclooxygenase-1 (COX-1) in platelets, preventing the production of thromboxane A₂ (TXA₂), a key promoter of platelet aggregation. Because the inhibition is irreversible, the effect lasts for the lifespan of the platelet (7–10 days).
Aspirin is also used as an analgesic and anti-inflammatory at doses of 500–1000 mg, but in lower doses it is used to treat and prevent cardiovascular events:
300 mg acutely to treat myocardial infarction.
75–300 mg daily for long-term prevention of infarction and stroke.
A known side effect is increased bleeding risk.
Mechanistically, in response to tissue damage, phospholipase A₂ releases arachidonic acid from membrane phospholipids. Arachidonic acid is then converted into unstable endoperoxides by cyclooxygenase (COX) enzymes. These endoperoxides are further processed into thromboxane A₂, prostacyclins, and prostaglandins. Therefore, blocking COX prevents the formation of these downstream mediators.
Calopidogrel
Binds irreversibly to P2Y12 (antagonists) receptor, preventing ADP action, platelet aggregation and activation. Oral route. Treats/prevents infarction but some studies say it’s not as effective as aspirin. Can cause bleeding, rash, diarrhoea
CPIIb/IIIA receptor antagonists
Intravenously as adjunct to aspirin and heparin to decrease early events in infarction. By antagonising the glycoprotein 2B3A, it stops fibrinogen from binding to receptors to stop aggregation e.g tirofiban and eptifibatide.
Streptokinase
Activates plasminogen, promoting fibrin degradation. Infused intravenously to decrease acute infarction, enhanced with aspirin. Originate from bacteria therefore, body builds antibodies 4 or more days after dose therefore, cannot be given after this time. Cannot be given for haemorrhagic stroke.
Prevention of infarction
Low dose apirin, B blockers, ACE inhibitors, AT1 receptor antagonists and statins. ACE inhibitors and AT1 receptor antagonists increase survival as do antiplatelet treatments such as low dose aspirin
Other considerations
1) In MI, percutaneous coronary interventions (involve stent/balloon into coronary artery) with GPIIIb/IIa antagonists is more effective than fibrinolytic drugs which are an alternative if percutaneous intervention is unavailable/unsuitable.
2) Heparins, hirudines and DOACs acts immediately while warfarin takes days but warfarin can be taken orally
3) Long-term oral therapy with GPIIb/IIIa receptor antagonists is not effective and may be harmful leads to increase bleeding risk.
4) Fibrinolytic drugs decrease mortality if given within 12 hr symptom onset of MI. Sooner = better results but 3hrs for thrombotic stroke.
lipoproteins
Dyslipidemia is characterised by increase triglycerides and LDL-cholesterol but decreases HDL.
Preclinical phase
Disregulation of lipid homeostasis is an early event that drives structural changes within circulation that leads to lipid accumulation in circulation. Resultant occlusions have deleterious effects in the performance of the CVD.
Aerobic training
Increases HDL and LDL causing slight or no total cholesterol levels. It stimulated LDL activity decreasing circulating triglycerides to increase chylomicrons and VLDL-TG breakdowns. Similar to how fibrates work. Also, increase fatty acid O2 where repeated stress of aerobic activity increasing mitochondria biogenesis = increase oxidative capacity = decrease circulating lipids. Improvements seen >150mins/week where effects are greatest in higher intensity aerobic exercise. Impacts more prominent in dyslipidemia patients. Impacts more prominent in dyslipidaemia patients.
