BISC 307L 2nd Edition Lecture 30 Current Lecture Hematopoiesis Blood cells come from the bone marrow Red bone marrow in fetal life create red blood cells After birth however most red bone marrow converts to yellow bone marrow except for a few of the long bones pelvis etc which retain the ability to make red blood cells The rest of the bone marrow is yellow bone marrow which is used in fat storage You have various levels of commitment of stem cells top left pluripotent hematopoietic stem cells which proliferate and become uncommitted stem cells which become committed to give rise to certain mature blood types but remain stem cells and continue to proliferate One of the daughter cells then becomes fully committed becoming a progenitor of a full cell these are NOT stem cells they mature into mature cell types Neutrophils are shown as are RBC s and a megakaryocyte which stays in the bone marrow and buds off platelets Can see a monocyte which will give rise to a macrophage The hematopoiesis of these different cell types is controlled by hematopoietic cytokines hormones of the immune system One example is erythropoietin which stimulates the production of erythrocytes Another is thrombopoietin which stimulates the megakaryocytes and therefore the platelets to develop and then there are a variety of cytokines called colony stimulating factors or interleukines and they stimulate all the blood cell types in different ratios They are produced in prestigious numbers the most abundant blood cells are the erythrocytes have a life span of 90 120 days after which they are destroyed so there is a substantial production of RBC s all the time The cell type being produced at the highest rate are the neutrophils They have a life span of a few hours so they must be produced rapidly Hemostasis The viscosity of the blood can t be too high or it can t flow freely And it definitely should not clot if it clots incorrectly then resistance would go up greatly and problems would ensue But it also has to be able to clot to stop leaks Hemostasis the cessation of bleeding is a five step process 1 Vasoconstriction 2 Platelet plug formation 3 Coagulation 4 Tissue repair 5 Thrombolysis The process begins with damage to the wall of the blood vessel The damage to any smooth muscle cells that happen to be in the vessel is going to cause vasoconstriction which will minimize blood loss in that area left hand path Blood is normally only in contact with the endothelium except when the vessel is damaged Two abundant proteins in the layers of the blood vessel wall outside the lumen are collagen and tissue factor The exposure of collagen and tissue factor to platelets is going to trigger clotting Tissue factor is also known as coagulation or clotting factor three or thromboplastin When platelets contact collagen they bind to them by means of integrins which are membrane proteins that bind to certain 3 amino acid sequences in extracellular matrices on the outside of the cell There are also some changes inside the cell that cause the platelets to become sticky and adhere to each other These sticky mutually adhering platelets form a platelet plug which increases the resistance to the blood flowing out decreasing the flow and pressure In particular stuff oozing out initially is blood but then becomes serum plasma clotting factors that are being filtered through the spaces of the porous platelet plug Platelets do not aggregate in a healthy endothelium The intact endothelial cells secretes nitrous oxide which inhibits platelet adhesion and it converts some of the membrane lipids into an eicosanoid called prostacyclin Secretion of prostacyclin and N O inhibit platelet adhesion So no clots should form on a healthy endothelium Platelets also release platelet factors platelets are full of vesicles and they burst open releasing the contents which are three things 1 Platelet activating factor and 2 Serotonin and 3 ADP These platelet factors bind to receptors on other platelets activating them Platelet activating factor additionally causes the synthesis of an eicosanoid named thromboxane A 2 TA2 and serotonin are vasoconstrictors Release of platelet factors also enhancing vasoconstriction that s due to platelet activating factor activating synthesis of thromboxane A2 and serotonin being the vasoconstrictive agent that add to the vasoconstriction of vascular smooth muscle in the neighborhood Coagulation Cascade At the very bottom of the cascade we will end up with cross linked fibrin which will reinforce the platelet plug Fibrin fibrils are sticky and strong so that they stick to the wound and they adhere to each other and form a mesh that greatly reduces blood loss Once they ve polymerized from their subunits they began contracting or getting shorter pulling the edges of the torn vessel together sealing the vessel for good On the right is the extrinsic pathway involving mechanisms that are external to the blood itself Start with damage exposing tissue factor III which converts clotting factor VII to active VII Active VII is also an enzyme and along with tissue factor III they both activate IX to make it active IX There is also the intrinsic pathway on the left It includes tissue factor XII which is activated by binding to collagen and other substances XII is inactive and when it gets activated it catalyzes inactive XI to active XI Active XI catalyzes inactive IX to active IX At this point the pathways converge Active IX catalyzes conversion of X to active X which requires factor VIII as a cofactor along with calcium membrane phospholipids tissue factor III and active VII both stimulate it So everything converges again on formation of active X Active factor X is going to convert prothrombin to thrombin This is a Ca dependent step that also requires clotting factor V and PL phospholipids Where do all these inactive proteins prothrombin fibrinogen etc in the plasma come from They are all made by the liver Thrombin catalyzes the conversion of inactive fibrinogen to fibrin a structural protein And thrombin also feeds back positively and converts XI to active XI as does active X for VII Fibrin polymerizes to form long fibrils as well as catalyzing the conversion of XIII to active XIII which crosslinks fibrin to make the cross linked fibrin mesh Active VII and X promote tissue repair Notice the importance of Ca in many of these steps Tissue repair and thrombolysis The endothelium will repair themselves endothelial cells near the area of