Lec 9- anticoagulant Flashcards
Homeostasis: the arrest of blood loss from damaged blood vessels
Physiology
- Wounding: vasoconstriction; adhesion and activation of platelets to form a plug; coagulation cascade, reactions in blood
- Initiated: to form fibrin which reinforces plug to form clot
- Pathophysiology: thrombosis- the pathological formation of a haemostatic plug within the vasculature in the absence of bleeding
Normal haemostatic balance
- Pro coagulants and platelets –> failure to clot bleeding
- Naturally occuring anti-coagulants and good vascular flow (normally dominant) –> thrombosis
2 main processes in clot formation
1) platelet activation
2) fibrin production- coagulation cascade
1) platelet activation
NB PLATELET ACTIVATION IS LOCAL
1) CONTACT: Endothelium of the blood vessels break down allowing the platelets to come into contact with collagen in subendothelium
2) ADHESION: In response to this contact the platelets become sticky and adhere to one another
3) PROPERGATION: the aggregates then flatten out and form a layer of platelets- this step then attracts other platelets
4) RELEASE REACTION: The platelets then release chemicals (Ca, 5-HT, ADP, PAF, TXa2), attracting further platelets
5) AGGREGATION: layering of platelets causes formation of plug
6) Morphological step: the exposure of phospholipids, that aren’t normally active –> activation of proteases of the clotting system
7) FIBRIN PRODUCTION: Activation of clotting enzymes allows formation of fibrin which stabalises the plug allowing it to form a clot
Coagulation cascade In vivo
- Activated by tissue damage
- V||a (tissue factor)
- Zymogen X—> factor Xa
- Zymogen || is catalysed by Xa to form factor ||a thrombin
- ||a thrombin acts on fibrinogen –> fibrin -(X|||a act on fibrin) –> Insoluble fibrin
- Inactive prescursors (zymogens) are activated by proteolysis to become factors
Coagulation cascade In vitro
- Activated by non-biological agent e.g. glass
- –(X||a, X|a, |Xa act on X) —>
- the same as in vivo once you get to zymogen X
- The 2 pathways converge when turning X into Xa
Blood factor activation
- Activation of factors is catalysed by their binding to acid phospholipids (-ve charge) on activated platelets
- So platelets act as localising focus on factors (-ve charge due to carboxylation (X,||)
- The gamma-carboxylation of glutamic acid residues on the blood factors requires Vit K as a Co-factor, this makes factors -ve charge
- Ca2+ attracts phospholipids and factors with platelet allowing them to associate better
- Activation of prothrombin to thrombin by factor Xa
- Thrombin cleaves fibrinogen to form fibrin
Vitamin K(ogaulant)
- Factors ||, VII, IX, X ———> Gamma-carboxyglutamic acid
- Vit K —————————> Vit K- oxidised form
Platelet and clot formation
- ADP -(acts on) -> P2Y12
- P2Y12 -(activates) -> AA(arachidonic acid)
- AA –(COX) –>PGH2 (prostaglandin H2)
- PGH2 –(TX synthase) –> TXA2 (Thromboxane A2)
- TXA2 induces expression of glycoprotein IIB/IIIA receptors (these are receptors for fibrins)
- TXA2 is lipid soluble so can activate other platelets
- Fibrin strands bind to glycoprotein IIB/|||A receptors (these are the receptors expressed by TXA2)
Physiology
- Local damage –> platelet activation
- Local platelet activation –> local activation of blood factors
- Results in local clotting
Thrombosis- pathophysiology
-A thrombus can form in: arteries; veins and heart
+A healthy endothelium inhibits thrombus formation (this can be via external or internal damage)
-Arterial thrombus: large ‘head’ (white thrombus, leucocytes, platelets)
-Venous thrombus: small head, red tail, can break off- embolism
CAUSES: damaged endothelium (atherosclerosis to cause MI or stroke)
Static circulation- bed rode to cause deep vein thrombosis (DVT) in leg; AF to clot (embolism –> stroke)
Atherosclerosis
- Damage to the endothelium
- Causes inflammation and clotting of platelets
- Continual aggregation of platelets causes increase in clot size
- Clot can grow so big it blocks blood flow
- AMI or stroke
DVT
-Deep Vein Thrombosis
Symptoms: red swollen limb; usually below knee; pain in limb; warm skin
Diagnosis: D-dimer; doppler ultrasound; venogram
Embolus
- A portion of a thrombus (forming thrombus) which breaks off and is carried in the circulation
- Arterial embolism: blocks a dismal artery causing an infarct; Cerebral embolism- carotid artery causing stroke or AMI
- Venous thrombosis (DVT)- causes oedema and inflammation and may cause pulmonary embolism
Pulmonary embolism
Symptoms: shortness of breath; pain in chest; coughing; dizziness; fainting
Diagnosis: chest x-ray; D-dimer; ventilation-purfusion scan; computerised tomography pulmonary angiography (CTPA)
