BME 501Advanced Topics in Biomedical SystemsSpring 2014Dr. KayBME 501 Lecture Notes – Mar 12Overview of Circulation and Blood (cont.)• Components of the blood– Plasma– Blood Cells• Hemostasis– Primary– Secondary• Blood circuitryHemostasisIn response to blood vessel injury, three processes initiate to stem the flow of blood:1. Vasoconstriction (endothelium, smooth muscle cells)2. Platelet aggregation3. Blood coagulation (coagulation cascade)Vasoconstriction• Injury to a blood vessel elicits contractile response by vascular smooth muscle, resulting in narrowing of vessel• Vasoconstriction in severed arterioles (small arteries) can completely obliterate lumen of vessel to stop blood flow• Contraction of vascular smooth muscle is induced by direct chemical and/or mechanical stimulation (G-protein-coupled receptors, gated calcium ion channels, etc.) as well as by chemical and/or mechanical stimulation of perivascular nervesHemostasis• Following injury to a blood vessel, multiple clotting systems are activated • Hemostatic process is divided into 2 components:– Primary hemostasis: formation of platelet plug• Depends on response of platelets and blood vessel wall to injury• When small blood vessels are injured, platelets adhere and aggregate at site of injury, reducing and finally arresting bleeding – Secondary hemostasis: formation of fibrin mesh • Depends on coagulation cascade system• Involves circulating clotting factorsPrimary HemostasisCharacterized by - Adhesion of platelets to injured region of blood vessel- Activation of platelets (change shape, release pro-clotting factors)- Aggregation of plateletsVisual Representation of Primary HemostasisI. Normal Physiologic ConditionsEndothelium prevents hemostasis- Provides (smooth) physical barrier- Secretes platelet inhibitory products; e.g., prostacycline (PGI2) and nitric oxide (NO)Visual Representation of Primary HemostasisII. Endothelial Cell InjuryWith injury to endothelial cells- Exposure of von Willebrand factor (vWF) in subendothelium- Platelets adhere to vWF via glycoprotein Ib-IX (GP Ib-IX) on surface of platelet membrane- vWF important for platelet binding in regions of high shear rate (such as the microvasculature)Visual Representation of Primary HemostasisIII. Activation of PlateletsAdhesion activates platelets, causing- Shape change of platelets and commencement of “release reaction” (releasing contents of granules from inside platelets, including ADP and serotonin)- Activation of collagen receptors (glycoprotein IIb/IIIa) on surface of platelets - Binding of fibrinogen to active collagen receptors, effectively cross-linking platelets to form platelet plug- Synthesis and release of thromboxane A2(TXA2) and platelet activating factor (PAF); act as potent platelet aggregating agonists and vasoconstrictors- Movement of phosphatidylserine (PF3) to outer layer of platelet membrane, providing essential binding sites for activated coagulation factorsVisual Representation of Primary HemostasisIV. Primary Platelet PlugIn formation of primary platelet plug - Thromboxane A2, PAF, ADP and serotonin act as platelet agonists, causing activation and recruitment of additional platelets- Additional platelets bind to previously adhered platelets- Platelet aggregation mediated primarily by fibrinogen- Process is enhanced by generation of thrombin through coagulation cascade (acts as platelet agonist, and converts fibrinogen to fibrin)Primary platelet plug must be stabilized by formation of fibrinSecondary Hemostasis:Begins when cascade system of coagulation is activated by substances released at time of blood vessel injury(contact activation pathway)(tissue factor pathway)Coagulation Factors• Circulate in plasma as co-factors or pro-coagulants• When activated, supply some components needed for clot formation• Assigned roman numerals in order of their discovery; numbers do not correspond to their location in coagulation sequence of activation• Coagulation factors are generated in liver cells• Factor VIII (which associates with von Willebrand factor), also produced outside of liver, including in endothelial cells and possibly megakarocytes• Measure of extrinsic pathway of coagulation• Measures activity of Factors I (fibrinogen), II (prothrombin), V, VII, and X• Extrinsic factors not measured: Factors III (tissue factor or thromboplastin), and IV (Ca2+)• Used to determine clotting tendency of blood (e.g., to evaluate warfarin dosage, liver damage, vitamin K status, clotting disorders)• Normal/reference range of 12-13 seconds to clot after Factor III (tissue factor) is added to the sampleClinical Application:Prothrombin Time (PT)Clot Lysis: Fibrinolysis• After wound has healed, clot is destroyed by plasmin (produced in inactive form, plasminogen)• Plasminogen has affinity for fibrin, is incorporated into aggregate of cells/coagulation factors while clot is being formed• Plasminogen converted to plasmin by tissue plasminogen activator (tPA), urokinase, and several factors from coagulation cascade• Plasmin cuts fibrin mesh in various locations, resulting in free-floating fragments that are cleared by kidney, liver, and circulating proteases• Balance of clot formation and clot lysis is very important; imbalance in either direction can lead to excessive clotting or bleedingPlasminogenFibrinolysis: mediated by activation of plasminogen to plasminPrimary fibrinolysis (endogenous):Intrinsic activation (plasma based)Initiated by way of Factors XIa, XIIa, and Kallikrein (all from intrinsic coagulation cascade)Extrinsic activation (cellular based)Initiated by way of stimuli such as vascular injury, ischemia, exercise, stress and pyrogens (e.g., tPA is slowly released into blood by damaged blood-vessel endothelium)Secondary fibrinolysis (exogenous):Therapeutic activation (drug based) Include streptokinase (produced by bacteria), urokinase and tPA (endogenous, but can be given as drug)SummarySummaryClot lysisAt equilibriumBlood coagulationBlood coagulationClot lysisBleedingBlood coagulationClot lysisBlood clotsKey Concepts of HemostasisThe CircuitryCardiovascular system:• Heart: pump• Arteries and veins: series of distribution and collection tubes• Capillaries: extensive system of thin vessels permitting rapid exchange of substances between tissues and vascular channelsArrangement of Blood Vessels• Vessels in parallel and series• Pulsatile flow in arteries• Laminar flow