Chapter 16 Blood About this Chapter Composition of Blood Plasma make up and roles
Various cell types, origin and roles Red blood cells, hemoglobin & iron metabolism How coagulation works Blood Components: Plasma Transports Solutes
Water, ions, trace elements Gasses: O2 & CO2 Organic Molecules Glucose Nwastes Proteins Antibodies Hormones Composition of Blood 55% of our blood's volume is made up of plasma
Plasma also contains blood clotting factors, sugars, lipids, vitamins, minerals, hormones, enzymes and antibodies One groupdetected 490 separate proteins in serum Serum albumin accounts for ~55% of blood proteins, globulins make up ~38% and fibrinogen comprises ~7% The remainder of plasma proteins (1%) consists of regulatory proteins such as enzymes, proenzymes and hormones. All blood proteins are synthesized in liver except for the gamma globulins. Plasma contains many thousands of distinct lipid molecular species that fall into six main categories including fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterols, and prenols The cellular components of blood include red corpuscles (erythrocytes), platelets (thrombocytes), and five types of white corpuscles (leukocytes) Blood Components: Plasma Transports Solutes
Figure 16-1: Composition of blood Blood Components: "Blood Count" % of Each Component
Figure 16-2: The blood count Blood Components: Cells
Erythrocytes Red Blood Cells (RBC) O2 & CO2 transport White Blood Cells (WBC) Immune defense Phagocytosis Platelets: clotting Blood Components: Cells
Figure 16-1: Composition of blood Hematopoiesis: Blood Cell Formation
Mostly in bone marrow from stem cells Rate regulated by cytokines & growth factors Hematopoiesis: Blood Cell Formation
Figure 16-3: Hematopoiesis Focus on RBCs: Lose their nucleus Cytoskeleton shape Hemoglobin
Binds O2 in heme group Binds some CO2 on globulin Focus on RBCs: Figure 16-5c: Bone marrow Figure 16-7a, b: Bone marrow
Focus on RBCs: Figure 16-7a, b: Bone marrow Iron Metabolism: Key to Hemoglobin O2 Transport
Figure 16-8: Iron metabolism Some Diseases of RBCs and O2 Transport
Table 16-3: Causes of Anemia Blood Components: Platelets
Coagulate, form plug, prevent blood loss Formed by fragmentation from megakaryoctyes Figure 16-10c: Megakaryocytes and platelets Overview of Hemostasis: Clot Formation & Vessel Repair
Figure 16-11: Overview of hemostasis and tissue repair Hemostasis: Vasoconstriction & Plug Formation
Platelet activation Multiple factors Positive feedback Aggregation Loose plug Hemostasis: Vasoconstriction & Plug Formation
Figure 16-12: Platelet plug formation Hemostasis involves the interaction of:
Vascular Endothelium Platelets Coagulation Factors and Fibrinolytic Proteins Hemostasis has 2 main functions:
Induce a rapid & localized hemostatic plug at the site of vascular injury (clot formation) Maintain Blood in a fluid, clot-free state after the injury is healed (clot dissolution) Endothelium vs. subendothelium
Endothelial cells line the vessels. Are thromboresistant in nature. They express thrombomodulin and heparin sulfate to keep inappropriate thrombi from forming. They also release tissue plasminogen activator and urokinase in the presence of thrombin shut off the coagulation cascade in the presence of IIa (thombin). Subendothelium beneath the endothelium. Are thrombogenic in nature. Express von Willebrand Factor (vWF), collagen, and tissue factor to kick off the coagulation cascade. Subendothelium Endothelium Source: Beginning ReviewQuiz Primary Hemostasis Injury Endothelial Cells
Exposure of thrombogenic surface (subendothelial extracellular matrix) Platelets adhere and get activated Change shape
Release secretory granules (e.g. ADP, TXA2) Attract other platelets and Aggregate Hemostatic plug or Primary Platelet Plug Secondary Hemostasis Fibrin is required to stabilize the primary platelet plug Fibrin is formed by two coagulation pathways i.e. Extrinsic & Intrinsic Extrinsic Pathway is initiated when Tissue Factor (III) present in damaged organ comes in contact with Blood Intrinsic Pathway is initiated when Factor XII binds to a negatively charged foreign surface exposed to Blood Hemostasis: Coagulation & Clot Stabilization
Prothrombin Ca++ Fibrinogen Fibrin Polymerization Figure 16-13: The coagulation cascade Clinical Significance of Intrinsic and Extrinsic Pathways
Two pathways lead to the formation of a fibrin clot: the intrinsic and extrinsic pathway. Although they are initiated by distinct mechanisms, the two converge on a common pathway that leads to clot formation. Both pathways are complex and involve numerous different proteins termed clotting factors. Fibrin clot formation in response to tissue injury is the most clinically relevant event of hemostasis under normal physiological conditions. This process is the result of the activation of the extrinsic pathway. The formation of a red thrombus or a clot in response to an abnormal vessel wall in the absence of tissue injury is the result of the intrinsic pathway. The intrinsic pathway has low significance under normal physiological conditions. Most significant clinically is the activation of the intrinsic pathway by contact of the vessel wall with lipoprotein particles, VLDLs and chylomicrons. This process clearly demonstrates the role of hyperlipidemia in the generation of atherosclerosis. The intrinsic pathway can also be activated by vessel wall contact with bacteria. PT and aPTT testing PT (Prothrombin Time) test is done for deficiency of factors of extrinsic pathway aPTT (activated Partial Thromboplastin Time) test is done for deficiency of factors of Intrinsic pathway Pharmacologic considerations
PT (prothombin time) measures the function of the extrinsic pathway and the common pathway. Extended by warfarin. aPTT (partial thomboplastin time) measures the function of the intrinsic pathway and the common pathway. In vitro extension by heparin. Vitamin-K dependent coagulation components Factors X, IX, VII, II, proteins C, S (mnemonic: 1972 [10, 9, 7, 2]). Warfarin (Coumadin) inhibits vitamin-K reductase and effective levels of of vitamin-K dependent coagulation components. Will extend the PT. Heparin (drug) purified from animals. Increases the activity of ATIII. Will increase the aPTT in vitro. Thromboxane A2 (TXA2) synthesis of TXA2 is initiated by activated platelets. TXA2 increases platelet activation and aggregation. Its synthesis is inhibited by aspirin. Beginning ReviewQuiz Overview of Traditional and Newer Antithrombotic Agents
Baron TH et al. N Engl J Med 2013;368: Constitutive inhibition
secondary hemostasis Extrinsic pathway Intrinsic pathway anticoagulation Constitutive inhibition Common pathway primary hemostasis Antifibrinolysis Thrombin INJURY! Platelet Plug Fibrin Fibrin clot Dissolving the Clot and Anticoagulants
Bleeding stopped Vessel repair Plasmin Fibrinolysis Clot dissolved Dissolving the Clot and Anticoagulants
Figure 16-14: Coagulation and fibrinolysis Fibrinolysis As soon as the injury is healed clot dissolution starts, to restore the normal flow of Blood Plasminogen is converted to the active form Plasmin by 2 distinct Plasminogen Activators (PAs): tissue plasminogen activator (t-PA) from injured endothelial cells Urokinase from Kidney endothelial cells and plasma Coagulation and Disease
Hemophilia Cardiovascular Diseases Key problem clots block undamaged blood vessels Anticoagulants prevent coagulation Keep platelets from adhering Prevent fibrin coagulation "Clot Busters":Prevent further clotting Speed fibrinolysis Limit tissue damage (heart, brain) DIC (Disseminated Intravascular Coagulation)
J. Mitra & Co. Ltd. DIC(Disseminated Intravascular Coagulation) Massive Injury or Sepsis Massive release of Tissue Factor III Excessive Activation of Thrombin Coagulation becomes systemic Annual Sales Conference 2005 (South & West) High consumption of Platelets, coagulation factors
Over production of fibrin clot Fibrin clot disseminates or spreads throughout the microcirculation Obstructing the blood flow to capillaries, smaller vessels Once again release of Tissue Factor
Lack of blood supply leads to tissue injury (decreased oxygenation, organ infarction & necrosis) Once again release of Tissue Factor Second time coagulation activation More consumption of coagulation factors and platelets Summary Blood is about 50% plasma, water solvent &solutes: ions, elements, gasses, proteins, wastes & nutrients White blood cells function in internal defense Iron in hemoglobin is key to RBC transport of O2 Platelet activation initiates clot formation Clotting prevents blood loss but is a problem in cardiovascular disease