Haemostasis 1 (2023-24).pdf

WEEK 25 MPharm Programme Haemostasis 1 Dr G Boachie-Ansah [email protected] Dale 113 ext. 2617 MPharm PHA112 Haemostasis WEEK Outline of Lectures 25 Haemostasis and its significance The key players in haemostasis The 4 steps of haemostasis Primary haemostasis Secondary...

WEEK 25 MPharm Programme Haemostasis 1 Dr G Boachie-Ansah [email protected] Dale 113 ext. 2617 MPharm PHA112 Haemostasis WEEK Outline of Lectures 25 Haemostasis and its significance The key players in haemostasis The 4 steps of haemostasis Primary haemostasis Secondary haemostasis or coagulation cascade Tertiary haemostasis or fibrinolysis Regulation of haemostasis Slide 2 of 54 MPharm PHA112 Haemostasis WEEK Learning Outcomes 25 At the end of this lecture, you should be able to: Define haemostasis and describe its physiological significance Describe the key steps involved in haemostasis Describe the coagulation factors and their key roles in haemostasis Describe the endogenous mechanisms for the tight regulation of haemostasis Appreciate how defects in haemostasis can lead to thrombotic & bleeding disorders Slide 3 of 54 MPharm PHA112 Haemostasis WEEK Haemostasis 25 Definitions Essentially, “the arrest of bleeding from a broken or ruptured blood vessel” (from ‘haemo’, blood; ‘stasis’, standing) a natural process & the body’s normal physiological response that prevents significant blood loss (bleeding or haemorrhage) after vascular injury an integral part of a complex and well-regulated system that keeps blood fluid and clot-free in normal blood vessels, but rapidly forms a localized plug in injured vessels Slide 4 of 54 MPharm PHA112 Haemostasis WEEK 25 Slide 5 of 54 MPharm PHA112 Haemostasis WEEK 25 Haemostasis Major Players in Haemostasis Haemostasis is a finely tuned process & a complex biochemical network Depends on an intricate series of events involving: The blood vessel wall Platelets & other blood cells Coagulation proteins & other proteins Slide 6 of 54 MPharm PHA112 Haemostasis WEEK Haemostasis 25 A 4-Step Process Localised vasoconstriction reduces blood flow to the injury site & retards blood loss Primary Haemostasis (platelet plug formation) plugs the breach in the blood vessel Secondary Haemostasis (blood clotting/coagulation) strengthens & reinforces the platelet plug Tertiary Haemostasis (Fibrinolysis) dissolves the clot once blood vessel integrity has been restored Slide 7 of 54 MPharm PHA112 Haemostasis WEEK Haemostasis 25 Localised vasoconstriction Injured blood vessel constricts Vasoconstriction mediated by reflex neurogenic mechanisms & released vasoconstrictors (e.g. endothelin) Transient – typically lasts for up to 30 mins Briefly reduces blood flow to the injury site & retards blood loss Slide 8 of 54 MPharm PHA112 Haemostasis Haemostasis WEEK 25 Primary Haemostasis Intact endothelium acts as a physical barrier separates circulating platelets from thrombogenic substances in the extravascular space Vascular injury exposes procoagulant subendothelial matrix to circulating platelets & initiates 4 events: Platelet adhesion Platelet activation Platelet aggregation Platelet plug formation Slide 9 of 54 MPharm PHA112 Haemostasis WEEK 25 Slide 10 of 54 MPharm PHA112 Haemostasis WEEK 25 Key Steps in Primary Haemostasis Platelet adhesion Upon endothelial injury, platelets bind to exposed subendothelial matrix proteins (e.g. collagen) Platelets bind adhesive proteins via transmembrane glycoprotein receptors GP1b-IX-V complex binds von Willebrand factor GPVI & α2β1 (GPIa-IIa) bind directly to collagen GP1c/IIa binds fibronectin Slide 11 of 54 MPharm PHA112 Haemostasis WEEK Platelet Adhesion 25 Slide 12 of 54 MPharm PHA112 Haemostasis WEEK 25 Key Steps in Primary Haemostasis Platelet activation Adherent platelets undergo a process of activation, leading to several key changes in platelets: Shape change – from their normal discoid shape to elongated cells with cytoplasmic extensions Granule release – release of contents of preformed cytoplasmic granules α-granules – contain vWf, P-selectin, FV & FXIII dense granules – contain ADP, serotonin & Ca++, etc Membrane phospholipid metabolism  increased thromboxane A2 (TXA2) production Activation & expression of GPIIb/IIIa receptors Slide 13 of 54 MPharm PHA112 Haemostasis Key Events During Platelet Activation WEEK 25 Slide 14 of 54 MPharm PHA112 Haemostasis WEEK 25 Key Steps in Primary Haemostasis Platelet aggregation & plug formation Agonist-activated platelet GPIIb/IIIa receptors bind fibrinogen  cross bridges with adjacent platelets  formation of a primary haemostatic plug The primary haemostatic plug is sufficient to stop haemorrhage in small blood vessels BUT not in larger vessels or vessels with severe injury The activated & aggregated platelets form the phospholipid membrane surface for the clotting process (Secondary haemostasis) Slide 15 of 54 MPharm PHA112 Haemostasis WEEK Primary Haemostasis 25 Platelet adhesion Platelet activation & aggregation Slide 16 of 54 MPharm PHA112 Haemostasis WEEK Primary Haemostasis 25 Platelet Activation & Aggregation Slide 17 of 54 MPharm PHA112 Haemostasis WEEK Primary Haemostasis 25 Platelet Activation & Aggregation Slide 18 of 54 MPharm PHA112 Haemostasis WEEK Primary Haemostasis 25 Platelet Adhesion, Activation & Aggregation Slide 19 of 54 MPharm PHA112 Haemostasis WEEK Primary Haemostasis 25 Platelet Adhesion, Activation & Aggregation Slide 20 of 54 MPharm PHA112 Haemostasis WEEK Primary Haemostasis 25 Platelet Adhesion, Activation & Aggregation Slide 21 of 54 MPharm PHA112 Haemostasis Haemostasis WEEK 25 Secondary Haemostasis Also called the Coagulation Cascade Main goal is to form a stable fibrin clot at the site of injury Involves serial activation of coagulation factors  formation of insoluble, cross-linked fibrin  stabilisation of the primary platelet plug  a compact, solid, irreversible clot (secondary haemostatic plug) Slide 22 of 54 MPharm PHA112 Haemostasis Secondary Haemostasis WEEK 25 The Coagulation Cascade Three key features: It is a sequence of enzymatic reactions involving blood-borne coagulation or clotting factors The major activation reactions require: A negatively charged phospholipid-rich membrane surface (on activated platelets, endothelial cells, etc) An enzyme (activated coagulation factor), a substrate (proenzyme form of downstream coagulation factor), a cofactor & Ca++ It is traditionally divided in 3 distinct pathways – the intrinsic, extrinsic & common pathways Slide 23 of 54 MPharm PHA112 Haemostasis The Coagulation Cascade WEEK 25 Coagulation or Clotting factors The coagulation cascade involves serial activation of inactive plasma proteins ( &  globulins) to active enzymes & cofactors Each activated enzyme reacts with the next inactive plasma protein to convert it into an active enzyme This proceeds until fibrinogen, the final substrate, is converted to fibrin by the activated enzyme, thrombin All the enzymes in the cascade are serine proteases Slide 24 of 54 MPharm PHA112 Haemostasis The Coagulation Cascade WEEK 25 Coagulation or Clotting factors (cont’d) The enzyme precursors, cofactors & other key factors involved in the cascade are referred to as coagulation or clotting factors 12 coagulation or clotting factors identified & designated with Roman numerals (I-XIII), according to the order of their discovery By convention, the activated form of coagulation factor is denoted by a lower case “a” after the factor number Most of the factors are synthesized in the liver Slide 25 of 54 MPharm PHA112 Haemostasis WEEK Coagulation or Clotting Factors 25 Slide 26 of 54 MPharm PHA112 Haemostasis WEEK 25 Slide 27 of 54 MPharm PHA112 Haemostasis WEEK 25 Biochemical & Physiological Classification of Coagulation Factors Group Coagulation Factors Basic Properties Contact Group XII, XI, prekallikrein, HMW Kininogen Require contact with negatively charged surface for activation Prothrombin Group II, VII, IX, X Require vitamin K for synthesis Fibrinogen Group I, V, VIII, XIII Large molecules Absent from serum Slide 28 of 54 MPharm PHA112 Haemostasis