Chapt. 45Inheritance of X-linked gene for Factor VIII hemophilia APlasma componentsAlbumin and other proteinsII. Other plasma proteinsIII. Plasma proteins maintain integrity of circulatory systemAdhesion of platelets to subendotheliumFibrinogen, fibrinB. Blood coagulation cascadeBlood coagulation processTable 45.2 Proteins of blood coagulationCrosslink fibrin monomersg-carboxyglutamate in clotting factorsRegulation of blood clottingSerpinsPlasminKey conceptsReview questionChapt. 45Ch. 45 Blood Plasma proteins, Coagulation and FibrinolysisStudent Learning Outcomes:•Describe basic components of plasma•Explain the formation of a blot clot (thrombus) – the cascade necessary for hemostasis and thrombosis:•the role of platelets, many factors, enzymes• Explain the effects of genetic defects of factors•Describe the regulatory mechanisms for the coagulation cascade, and antifibrinolysisInheritance of X-linked gene for Factor VIIIhemophilia APedigree of hemophilia transmission among Queen Victoria's descendantsHartl & Jones, GeneticsPlasma components1. Plasma proteins maintain proper distribution of water between blood and tissues•Plasma contains water, nutrients, metabolites, hormones, electrolytes, proteins•Same electrolyte composition as extracellular fluids•Many disease states alter plasma proteins – observe by electrophoresis•Osmotic pressure or plasma proteins is critical for bringing water back into blood from tissuesAlbumin and other proteinsAlbumin is major serum protein:•69-kDa glycoprotein, 60% of total plasma protein•Carries free fatty acids, zinc, Ca2+, steroid hormones, many drugsTable 1 other serum proteins made in liver:Ceruloplasmin binds copper, storageCorticosteroid-binding globulin binds cortisolHaptoglobulin binds extracellular hemeLipoproteins bind cholesterol and fatty acidsRetinol-binding protein binds vitamin ASex hormone-binding globulin binds estradiol, testosteroneTransferrin transports ironII. Other plasma proteinsImmune response involves plasma proteins:•Immunoglobulins (antibodies) made by B lymphocytes – bind specific antigens•Complement proteins aid in clearance of Ag-Ab;also bind bacterial cell wall and lyse through C3b• Activation of complement is a proteolytic cascadeProtease inhibitors in plasma control inflammatory responseIII. Plasma proteins maintain integrity of circulatory systemPlatelets are critical for clotting:If damage to endothelial lining of blood vessels exposes subendothelial layer: (Extracell matrix, smooth muscle cells)•Barrier (hemostatic plug, clot) forms•Platelets initiate, bind damage area•Clot formation is limited by regulation•Vessel heals, clot is degradedPlatelets from megakaryocyte (~8 nuclei) → 4000 non-nucleated plateletsAdhesion of platelets to subendotheliumPlatelets adhere to site of blood vessel injury:•Exposes collagen, vWF and other components(vWF (von Willebrand factor) is glycoprotein, is also in plasma, binds factor VIII to protect it; disorder → bleeding)•Then other GPs (glycoproteins) bind to fibrinogen, vWF•Platelet activation (release granules), brings more platelets (ADP is attractant); platelets release vasoconstrictorsFig. 1Fibrinogen, fibrinFibrinogen is cleaved to fibrin to form ‘soft clot’•Fibrinogen in blood and in platelet granules•Assists platelet aggregation (of activated platelets)•Cleavage by thrombin protease releases fibrin monomers which aggregate•Thrombin also binds platelets through receptor, activates them Fig. 2B. Blood coagulation cascadeThrombus (clot) is enhanced by thrombin activation •Proteins in plasma are proproteins (zymogens)•Activated by proteolytic cleavages, sequential •Highly regulated•Proenzymes: serine proteases:VII, XI, IX, X, prothrombin•Cofactor proteins bind:Tissue factor, V, VIII Fig. 3 PL, Ca are cofactors bound to phospholipids on platelet, vessel wall in Ca2+ complexBlood coagulation processFig. 3 positive feedback by thrombinBlood coagulation is complex cascade •Platelets adhere, plasma proteins react to subendothelium•Common path at Xa •Platelet membrane is scaffold for formation•-carboxylated clotting proteins chelate to membrane surface (- PL, Ca2+)•Thrombin is critical:•Positive feedback•Accelerate process•Cleaves XIII → XIIIaTable 45.2 Proteins of blood coagulationFactor descriptive name function/active formCoagulation factorsI Fibrinogen FibrinII Prothrombin Serine proteaseIII Tissue factor Receptor, cofactorIV Ca2+CofactorV Proaccelerin, labile factor CofactorVII Proconvertin Serine proteaseVIII Antihemophilia factor A CofactorIX Antihemophilia factor B Serine proteaseX Stuart-Prower factor Serine proteaseXI Plasma thromboplastin antecedent Serine proteaseXIII Fibrin-stabilizing factor Ca2+-dep transglutaminaseRegulatory factorsThrombomodulin endothelial cell receptor, binds thrombinProtein C activated by thrombomodulin-bound thrombin; serine proteaseProtein S cofactor; binds activated protein CCrosslink fibrin monomers1. Fibrin molecules cross link to form hard clot:•Thrombin forms Factor XIIIa•Factor XIIIa catalyzes transamidation reaction (Gln-Lys)•3D mesh of fibrin fibers traps platelets, cells•Factor XIIIa is only enzyme that is not a serine proteaseFig. 4carboxyglutamate in clotting factorsFig. 5Vitamin K is critical for clotting: •Coenzyme for -carboxyglutamate•Modified residues on clotting proteases, done in liver•Proteases bind platelets through the Ca2+ and PL-Assembly of factors, enzymes on complexes speeds up cascadeWarfarin, rat poison, inhibits carboxylase, resembles VitKRegulation of blood clottingFig. 6Thrombin has prothrombotic role: (Fig. 3)•Feedback amplification•Stimulates its own formation by activating factors V, VII, XI•Activates platelet aggregation, release factor VIII from vWF,Thrombin has antithrombotic role:•Binds thrombomodulin, abolishes function of thrombin •protein C and cofactor protein S form activated protein C (APC)•Destroy factors Va, VIIIaSerpinsSerpins: Serine protease inhibitors:•Natural products ~10% of plasma proteins•Each has reactive site like substrate, binds enzyme•Antithrombin III (AT III) inactivates Thrombin•Heparin (glycosaminoglycan) binds ATIII, allosteric enhance•ATIII-heparin also inactivates XIIIa, Xa, IXa, Xa proteases ATT III + heparinPlasmin Plasmin degrades clot – highly regulated process:•Plasmin is serine protease, from