Primary Exam Physiology lecture 5. Haemostasis

Transcription

1 Primary Exam Physiology lecture 5 Haemostasis

2 Haemostasis Body s response for the prevention and cessation of bleeding. Broadly consists of: Primary Haemostasis - vascular spasm and platlet plug formation Clotting of the plasma (secondary haemostasis) involving interaction between the numerous factors and inhibitors Fibrinolysis - process of removing clot once vessel integrity has been restored

3 Vascular Spasm Vasoconstriction by vascular smooth muscle cells and is the blood vessels first response to injury (endothelial damage). Controlled by vascular endothelium Reduces blood flow and limits the blood loss Platlet granules also promotes some degree of vasoconstriction

4 Platlets Endothelial damage - normally isolated collagen is exposed to platelets Occurs in three steps: Adhesion, Aggregation, Activation These platelets bind directly to collagen specific g1a/2b receptors This adhesion is strengthened by vwf and glycoprotien VI which further activates the platelets Activated platelets release stored granules - ADP, serotonin, platelet activating factor, vwf, Thromboxane A2 which activate other platelets in a cascade. Intracellular calcium levels increase and causes a process which increases the platelet affinity for fibrinogen binding which then forms cross links with the glycoprotien 2b/3a complex and completes primary haemostats These activated platelets also undergo a conformational change

5 Coagulation cascade Two pathways which lead to a third common pathway Contact activation pathway (Intrinsic pathway) tissues factor pathway (extrinsic pathway) Initially thought that both these pathways were equally important, but now we know that the tissue factor pathway is the more important of the two pathways

6 PICTURE

7 Tissue factor pathway Main role is to generate a thrombin burst - causes a rapid release of thrombin Damage to blood vessel - causes exposure of tissue factor Factor VII comes into contact with tissue factor and becomes activated (FVIIa) Factor VIIa activates IX and X The activation of FX to form Xa by the TF-FVIIa combination is inhibited by tissue factor pathway inhibitor Factor Xa and Factor Va form prothombinase which converts prothrombin into thrombin

8 Contact activation pathway Begins with the formation of the primary complex on collagen by high molecular weight kininogen (HMWK), prekallikrein and FXII. Prekallikrein is converted to kallikrien and factor XII becomes Factor XIIa Factor XIIa converts factor XI into XIa which then converts X to Xa and activates IX to IXa Factor IXa combines with its cofactor VIIIa to form a tenase complex that propagates the conversion of X to Xa.

9 Co Factors Calcium and phospholipid Required for the tenase and prothombinase complexes to function. Vitamin K Adds a carboxyl group to glutamic residues on factors II, VII, IX and X and Protein C, S and Z In addition vitamin K is also oxidised, and the enzyme Vit K epoxide reductase which reduced Vitamin K back to its active form Important for warfarin

10 Regulators Protein C Major physiological anticoagulant Vitamin K dependent Activated by thrombin and thombomodulin Degrades factor Va and VIIIa and prevents the formation of further thrombosis Antithrombin Serine protease inhibitor - degrades the serine proteases: thrombin, FIXa, FXa, FXIa and FXIIa > it is constantly active, but its adhesion to these factors is increased by the presence of heparin sulphate or the administration of heapins Tissue Factor Pathway Inhibitor Limits the action of tissue factor > and inhibits excessive TF - mediated activation of Factor VII and FX

11 Fibrinolysis Primary Fibrinolysis - normal body process Secondary Fibrinolysis - due to a breakdown of clots due to medication, or medical disorders The fibrin clot is broken down by plasmin and the remaining products are cleared by other proteases and excreted in the kidney and liver

12 Fibrinolysis Plasmin is produced in an inactive form: plasminogen in the liver Plasminogen cannot cleave fibrin, but it still has an affinity for it and it incorporated into the clot when it is formed t-pa and urokinase are the agents that convert plasminogen to the active plasmin and thus allow fibrinolysis to occur t-pa is released into blood by damaged endothelium It is released slowly so that over may days the clot is broken down

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14 Coagulation Studies PTT (Partial thromboplastin time) or aptt - intrinsic pathway (contact pathway) I, II, V, VIII, IX, X, XI, XII PT measures the speed of clotting via the extrinsic pathway Measures Fibrinogen, Prothrombin, V, VII and X PT/ISI = INR

15 Coagulation Studies Mixing studies - blood plasma used to distinguish factor deficiencies from factor inhibitors such as lupus anticoagulant or specific factor inhibitors such as antibodies directed against factor VIII If the problem is a factor deficiency then the patients plasma is mixed 1:1 with plasma that contains 100% of normal factor levels results in a level > 50% The PT will be normal (the mixing study shows correction) and this indicates a factor deficiency, a failure to correct indicates an inhibitor.

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