CVS Pathology 11 to 20
Describe the role of platelets in haemostasis.
- vWF acts as bridge b/w platelet surface receptors and exposed collagen. Platelets adhere and become activated
- Secretion (release reaction)
- Platelet granules (alpha granules + dense bodies). Factors released: calcium, ADP, ATP, histamine, serotonin, adrenaline, fibrinogen, factors V and VIII and TxA2 etc). Calcium required for coagulation cascade and ADP andTxA2, potent mediator of aggregation. Activation leads to surface expression of phospholipid complexes critical binding Ca and clotting factors forintrinsic clotting pathway. Injured or activated endothelial cells expose tissue factor which activates extrinsic clotting pathway.
- Stimulated by ADP and vasoconstrictor TxA2 .Enlarging platelet aggregate =primary hemostatic plug (reversible). Coagulation cascade activated.Thrombin cause further aggregation. Platelet contraction creates theirreversible secondary hemostatic plug. Thrombin converts fibrinogen tofibrin which cements platelets in place
- Bold to pass
Give an overview of the coagulation cascade.
- Component of haemostasis resulting in thrombosis (with endothelium + platelets)
- Series of enzymatic conversions
- Proenzymes converted to activated enzymes resulting in formation of Thrombin
- Comprises extrinsic and intrinsic pathways
- *Extrinsic pathway – activated by Tissue Factor (lipoprotein), exposed at sites of tissue injury
- Intrinsic pathway – activated by Factor XII
- *Pathways converge where activation of Factor X occurs
- *Common pathway – factor X, Prothrombin, Thrombin, factor V, Calcium, then fibrinogen converted to fibrin and ultimately cross linked fibrin
- *Bold to pass
Describe the role of platelets in coagulation?
- Vascular injury – extracellular matrix constituents, especially collagen.
- Adhesion: vWF bridges, stabilises initial platelet adhesion;
- Secretion (release reaction): from two types granules: – Ca, ADP key to aggregation; phospholipid complex key to intrinsic path.
- Aggregation: – primary hemostatic plug. Coagulation cascade –> thrombin –> then platelet contraction. Fibrin stabilises the aggregate
- 3 out of 4
Describe the pathogenesis of Disseminated Intravascular Coagulation.
- Variety of diseases activate the coagualtion system
- –> microthrombi
- –> injury to microvasculature of organs;
- consumption of clotting factors;
- activation of fibrinolysis
- –> bleeding.
- Release of tissue factor or thromboplastic substances;
- Widespread injury to endothelial cells
What major disorders might precipitate DIC?
- Obstetric complications; infections; neoplasms; massive tissue injury; miscellaneous: shock, snakebite, heat stroke, burns et
Describe factors that inhibit activation of the coagulation cascade.
- Antiplatelet: Intact endothelium; endothelial PGI2, NO; adenosine diphosphatase degrades ADP
- Anticoagulant: membrane associated heparins allow antithrombin 111 to inactivate factors; thrombomodulin allows thrombin to activate protein C, which requires protein S to be anticoagulant.
- Fibrinolytic: endothelial cells synthesize t-PA
Describe the pathogenesis of an aneurysm.
- Structure or function of the vascular wall connective tissue is compromised
- Poor intrinsic quality of the vascular wall connective tissue eg Marfan syndrome, Ehlers-Danlos
- Collagen degradation vs synthesis by local inflammation ( proteolytic enzymes) eg atherosclerotic plaque, vasculitis
- Loss of vascular smooth muscle cells or the inappropriate synthesis of noncollagenous or nonelastic ECM (cystic medial degeneration)
What are the clinical consequences of an AAA?
- Rupture into the peritoneal cavity or retroperitoneal tissues with massive, potentially fatal haemorrhage.
- Obstruction of a branch vessel resulting in ischemic injury, eg. iliac, renal, mesenteric, or vertebral arteries
- Embolism from atheroma or mural thrombus
- Impingement on an adjacent structure, e.g. ureter, vertebrae
- Nothing (if < 4cm and no embolic complic’s)
What is the risk of rupture of an AAA?
- Related to size
- 4 cm or less in diameter nil
- between 4 and 5 cm 1% per year
- between 5 and 6 cm 11% per year
- greater than 6 cm in diameter 25% per year
What is the coagulation cascade?
- The coagulation cascade is essentially a series of conversions of inactive pro-enzymes to activated enzymes, culminating in the formation of thrombin which then converts the soluble plasma protein fibrinogen into the insoluble fibrillar protein fibrin
- Bold to pass
What mechanisms restrict the activity of the coagulation cascade?
Prompt: How is fibrin broken down?
- Restriction of factor activation to sites of exposed phospholipids
- Three types of natural anticoagulants
- Antithrombins (e.g. AT3)
- Inhibit the activity of thrombin & other serine proteases (IXa, Xa, XIa, XIIa)
- AT3 activated by binding to heparin like molecules on endothelium ? utility heparin in thrombosis
- Proteins C & S
- Vit K dependant proteins characterised by ability to inactivate factors Va and VIIIa.
- Plasmin (fibrinolytic system)
- Plasminogen to plasmin by factor XII dependant pathway or 2 groups of plasminogen activators (PA) u-PA or t-PA
- Breaks down fibrin & interferes with polymerisation
- Resulting fibrin split products (fibrin degradation products) also act as weak anticoagulants
- Endothelial cells modulate the coagulation / anticoagulation cascade balance by releasing PAI
- block fibrinolysis by inhibiting t-PA binding to fibrin
- Antithrombins (e.g. AT3)
- Tissue factor Pathway Inhibitor (TFPI)
- Plasmin + 1 other
- Description of plasmin action
What conditions predispose to the development of pulmonary thrombo-embolism?
- Hypercoagulable States:
- Primary- factor V Leiden, prohtrombin 20210 A, hyperhomocysteinaemia, antiphospholipid syndrome
- Secondary – obesity, recent surgery, cancer, oral contraceptive pill, pregnancy
- Other underlying medical conditions – hip fracture, immobilization, cardiac disease, central venous lines
- Simple list of 6 = straight pass
- Better pass with bold groups and examples of each
What are the potential clinical sequelae of pulmonary thrombo-embolism?
Relates to size and number of emboli and overall status of cardiovascular system
- Sudden death
- Large PE –chest pain, dyspnoea, shock
- Small PE-transient chest pain, cough and in predisposed individuals pulmonary infarct causing tachycardia, tachypnea, haemoptysis, fever,pleural rub.
- Pulmonary hypertension
- Any 3 to pass
What are the non-thrombotic types of pulmonary embolism?
- Bone marrow or Fat
- Amniotic fluid
- Foreign bodies
- Any 3 to pass
What are the causes of pericarditis?
- Infectious, Inflammatory, Malignant
- Example of each.
- Non-infectious inflammations (Rhfever, SLE, uremia), viral;
- Fibrinous reaction occurs with these, plus AMI, post AMI;
- Pus from adjacent invasion, haem spread, lymphatic spread, surgical introduction;
- Blood from TB, malignant spread, bacteria, post-surgery; caseous is TB
- Bold PLUS example of each
What pathological types of pericarditis can occur?
- purulent (suppurative);
- 3 out of 5 to pass
Describe the pathological changes in myocardium following occlusion of a coronary artery.
- Loss of contractility (<2mins); loss of ATP (50% at 10min, 10% at 40min); irreversible cell injury (20-40min); microvascular injury (>1hour); coagulative necrosis.
- Minutes: myofibrillar relaxation, glycogen depletion, mitochondrial and cell swelling.
- 40minutes: sarcolemmal disruption, mitochondrial amorphous densities.
- Necrosis first in subendocardium, endocardium is spared. 4-12hour coag necrosis, edema, haemorrhage
What are the potential consequences of reperfusion?
- Early: no damage.
- Late: reperfusion hemorrhage; acceleration of disintegration of damagedmyocytes; exaggerated contraction of myofibrils; some new injury from oxygen free radicals.
- ‘Prolonged post-ischaemic ventricular dysfunction’