3- Primary Hemostasis - 2.pdf

Primary Haemostasis Role of Platelets  Function of Platelets The platelets functions include: A-The formation of mechanical plugs during the normal haemostatic response to vascular injury by: Platelet adhesion and activation. Platelet aggregation. Platelet release...

Primary Haemostasis Role of Platelets  Function of Platelets The platelets functions include: A-The formation of mechanical plugs during the normal haemostatic response to vascular injury by: Platelet adhesion and activation. Platelet aggregation. Platelet release reaction and amplification. Clot formation and retraction. B- Surveillance of blood vessel stability by: Checks endothelial lining for gaps and breaks. Fill in small gaps caused by the separation of endothelial cells. C- Aid in healing injured tissue  Platelet adhesion It is the binding of platelet to non-platelet surface. Platelets bind through specific membrane receptors to cellular and extracellular matrix constituents of the vessel wall and tissues. Involves changes from a disc shape to a slightly broader, plate-like form to increase surface area. Following blood vessel injury, the exposed subendothelial matrix is contained collagen and vWF. The platelets adhere to an extracellular matrix with vWF via the GP Ib-IX-V complex. The platelets also directly adhere to collagen via the GPIa/IIa. Adhesion is reversible & No ADP is released.  What is Von Willebrand Factor? vWF is a multimeric protein synthesized by endothelial cells and megakaryocytes. it is contained in Weibel-Palade bodies of endothelial cells, α- granules of platelets, in soluble form in plasma, as well as in the subendothelial matrix. Function of vWF: It’s involved in platelets adhesion to the vessel wall It’s involved in platelets aggregation It also carries and protects factor VIII.  Platelet Adhesion Molecules Platelets contain a number of adhesion molecules both on the plasma membrane and within granules that are relevant for hemostasis and thrombosis, as well as cell-cell and cell-subendothelial matrix interactions. 1- P-Selectin 2- Glycoprotein Ib/IX/V (GPIb/IX/V) 3-Glycoprotein IIb/IIIa (αIIbβ3) 4-Collagen Receptors (α2β1 integrin and glycoprotein VI) Substrates and receptors for platelet adhesion to the vessel wall Platelet adhesion to collagen Different collagens are present in the vessel wall. Of these, types I, III, and VI are known to support platelet adhesion and aggregation. Collagen-binding proteins, including: The integrin α2β1 (GP Ia/IIa in the pre-integrin era) GP VI GP IV (CD-36).  Substrates and receptors for platelet adhesion to the vessel wall Platelet adhesion to fibrinogen/fibrin: Fibrinogen is present in blood and contained within the α-granules of platelets. As such, fibrinogen is required for normal platelet aggregation selectively mediated by αIIb/β3. Fibrin has the ability to support platelet adhesion, and in so doing may synergize with immobilized vWF bound to its GPIb receptor. Platelet adhesion to fibronectin: Fibronectin is an essential adhesive substrate in many fundamental biological processes. Platelets possess two main receptors for this protein, α5/β1 and αIIb/β3 The α5/β1 supports platelet adhesion to endothelial ECM  Substrates and receptors for platelet adhesion to the vessel wall Platelet adhesion to thrombospondin: Thrombospondins are a family of adhesive proteins, of which thrombospondin-1 is contained in platelet α-granules. After activation-induced secretion, thrombospondin-1 binds to the platelet membrane and mediates adhesion. Platelet adhesion to laminin: Different forms of laminin are highly expressed in the subendothelial ECM. It has been reported that platelets can adhere to laminin  Endogenous Mechanisms Preventing Platelet Adhesion to Endothelium Various mechanisms prevent adhesion of platelets to endothelial cells under normal conditions; these are Nitric Oxide. NO-induced inhibition of platelet adhesion and activation Prostacyclin a potent inhibitor of platelet adhesion and aggregation Ecto-adenosine diphosphatase (ADPase) Endothelial Surface Layer (glycocalyx)  Platelet Activation Platelets undergo a shape change from disc to spiny sphere with projections. Activation continues until Ca ++ threshold met. Outcome Activation of GP IIb/IIIa receptors for fibrinogen. Secretion of granules within platelets into tissues.  Platelet Secretion & Release It is the release of contents of the granules of platelet  Serotonin: enhances vasoconstriction ADP: stimulates aggregation Fibrinogen: PLT aggregation vWF: PLT adhesion  Thrombospondin: PLT aggregate stabilizer  Fibronectin: PLT binding Plasminogen: source of plasmin PAI-1: inhibits activation of fibrinolysis α2-antiplasmin: plasmin inhibitor PF4: inactivates heparin PLT-derived Growth Factor (PDGF): tissue repair  Platelet aggregation It is characterized by cross-linking of platelets through active GPIIb /IIIa receptors with fibrinogen bridges. Calcium must be present Irreversible once platelet aggregate they do not disaggregate. Aggregation is also a response to helps initiation of the coagulation mechanism Aggregation is triggered by: PLT factor 3. Adenosine diphosphate (ADP) Thrombin Thromboxane A2 Collagen Platelet aggregation Resting Platelet Aggregated Platelets GPIIb/IIIa (inactive) GPIIb/IIIa Agonist (activated) e.g. ADP TXA2 thrombin Fibrinogen  Arachidonic Acid Cyclo-oxygenase Cyclic Endoperoxides PLATELET ENDOTHELIAL CELL Thromboxane Prostacyclin synthetase synthetase Prostacyclin Thromboxane (PGI2) (TxA2) Inhibits plt aggregation Enhances plt aggregation Vasodilator Vasoconstrictor  Platelet Agonists Agonists are substances that can attach to a platelet membrane receptor and activate platelets causing them to aggregate which include: ADP activates P2Y12 and P2Y1 receptors on plts Collagen activates GPIa/IIa and GPVI receptors Thrombin activates PAR1 and PAR4 receptors Epinephrine activates α2A receptor Arachidonic acid activates TPα receptor Thromboxane A2 activates TPα receptor Ristocetin causes plts agglutination via GPIb/IX/V complex  Clot formation and retraction Exposure of sub-endothelial collagen upon vessel injury activates platelets and also initiates coagulation resulting in the production of thrombin. Thrombin is a potent platelet agonist. The activated platelet secrets pro-thrombotic factors, causing an increased affinity of the fibrinogen receptor(αIIb/β3) for its ligand fibrinogen. Clot retraction results in the contraction of the fibrin network. The contraction of the fibrin clot results in the blood clot becoming smaller and excess fluid is squeezed out. This draws the edges of damaged tissue together and forms a mechanically stable clot. Thank you