Haemostasis Lecture Slides (Aston University)

Haemostasis – Part II Secondary Haemostasis Dr Caroline Kardeby Lecturer in Biosciences [email protected]  Preparation For this lecture you’ll need… To have listened to Write pathways in a way Caffeine! lecture on that makes most s...

Haemostasis – Part II Secondary Haemostasis Dr Caroline Kardeby Lecturer in Biosciences [email protected]  Preparation For this lecture you’ll need… To have listened to Write pathways in a way Caffeine! lecture on that makes most sense to you Haemostasis Part I  Aims and Objectives Outline the processes involved in normal haemostasis Following this lecture you should be able to: 1. Explain the importance of effective haemostasis 2. Describe the major components of haemostatic mechanisms 3. Describe the mechanisms of secondary haemostasis  Primary and Secondary Haemostasis Primary haemostasis Secondary haemostasis 1. Platelets respond to the vessel wall 1. Activation of the intrinsic and injury extrinsic coagulation pathways 2. Platelets adhere to the vessel wall 2. Activation of the common pathway 3. A primary platelet plug is formed 3. Fibrin strand formation and strengthening of the platelet plug All phases are integrated and many occur simultaneously  Secondary Haemostasis Weak platelet plug needs strengthening by coagulation factors (secondary haemostasis) Coagulation factors are mostly proenzymes (zymogens) Most coagulation factors are synthesised in the liver Vitamin K-dependant – Factors II, VII, IX, and X Proenzymes require activation to carry out their function Active form of a coagulation factor is denoted ‘a’  Secondary Haemostasis Secondary haemostasis happens in a 4-stage process: 1. Tissue factor is expressed or released 2. Activated platelets express phospholipid complexes with a negative charge where coagulation factors can bind and become activated 3. Conversion of prothrombin to thrombin 4. Conversion of fibrinogen to fibrin  Breakdown Theof the coagulation Coagulation Cascade cascade The coagulation cascade can be described to include three different pathways: 1. Extrinsic Pathway 2. Intrinsic Pathway 3. Common Pathway To understand how medicines that prevent blood clots function Assists understanding of in vitro diagnostic tests  Extrinsic Pathway Initiation – Vascular injury Physical injury Inflammation Atherosclerotic plaques Leads to Tissue Factor (TF) Surface receptor expression: FVII Fibroblasts, platelets and sometimes (plasma activated endothelial cells protein) Binds to + proteases FVIIa TF-FVIIa Extrinsic tenase Complex (mostly on cell surface) Activation Common FX FXa Pathway  Intrinsic Pathway Initiation – “Contact pathway” Contact with negative surfaces – in the laboratory Contact with negative subendothelial matrix components (collagen etc.) Contact with negatively charged phospholipids on the platelet surface – IMPORTANT LINK TO PRIMARY HAEMOSTASIS Activates FXII FXIIa Plasma negatively protein charged surface Activates FXI FXIa plasma protein Activates (by cleaving) FIX FIXa + FVIII FIXa-FVIIIa negatively charged + Ca2+ surface Activates Common FX FXa Pathway  Common Pathway Intrinsic Pathway Extrinsic Pathway Leads to Leads to FX FXa FX + FVa + Ca2+ Very strong platelet activator. Cleaves Prothrombin Thrombin (FII) (FIIa) Cleaves Fibrinogen Fibrin Stabilised (FI) (FIa) blood clot  What happens to the clot afterwards? When the injury is healed, the clots gets removed by fibrinolysis. Tissue plasminogen Tissue plasminogen activator (tPA) is an activator (tPA) enzyme that is secreted from endothelial cells. Cleaves tPA cleaves the abundant plasma zymogen called Plasminogen Plasmin plasminogen into its active form plasmin. Cleaves The breakdown of fibrin results into small fragments known as d-dimer to be formed. Fibrin Recombinant tPA and plasminogen activators are Leads to currently the only pharmacological treatment available after a thrombotic stroke has occurred. d-dimer  Why do we not get clots all the time? Both the intrinsic and the extrinsic pathway lead to thrombin generation, and thrombin activates platelets. Haemostasis is a tightly controlled process. Endogenous inhibitors of primary haemostasis: Nitric oxide is continuously synthesised from endothelial cells – a very strong platelet inhibitor. Prostacyclin (PGI2) is produced in endothelial cells – a very potent platelet inhibitor.  Why do we not get clots all the time? Endogenous inhibitors of secondary haemostasis: Tissue factor pathway inhibitor (TFPI) is expressed in cells surrounding the vasculature and in resting platelets. TFPI binds to FXa and inhibits the TF-FVIIa complex. Antithrombin III is a plasma protein that is produced in the liver and is an inhibitor of thrombin, FIXa, and FXa. Protein C is a plasma protein that is activated by thrombin. Activated protein C inhibits FVa and FVIIIa and prevents thrombin formation.  Summary Secondary haemostasis can be split into the extrinsic, intrinsic and common pathways. Clotting factors proceed in a cascade and generates a fibrin clot. Fibrin and activated platelets form a thrombus. Thrombus is digested by the enzyme plasmin, giving rise to d-dimer. Source: National geographic