Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Dee Unglaub Silverthorn, Ph.D.
H UMAN P HYSIOLOGY H UMAN P HYSIOLOGY
PowerPoint
®Lecture Slide Presentation by
Dr. Howard D. Booth, Professor of Biology, Eastern Michigan University
AN INTEGRATED APPROACH
T H I R D E D I T I O N
Chapter 16 Chapter 16
Blood
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About this Chapter 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
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Composition of Blood 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 group detected 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)
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Blood Components: Plasma Transports Solutes Blood Components: Plasma Transports Solutes
• Water, ions, trace elements
• Gasses: O 2 & CO 2
• Organic Molecules
• Glucose
• N–wastes
• Proteins
• Antibodies
• Hormones
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Blood Components: Plasma Transports Solutes Blood Components: Plasma Transports Solutes
Figure 16-1: Composition of blood
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Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Blood Components:
"Blood Count" – % of Each Component Blood Components:
"Blood Count" – % of Each Component
Figure 16-2: The blood count
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Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Blood Components: Cells Blood Components: Cells
• Erythrocytes
• Red Blood Cells (RBC)
• O 2 & CO 2 transport
• White Blood Cells (WBC)
• Immune defense
• Phagocytosis
• Platelets: clotting
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Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Blood Components: Cells Blood Components: Cells
Figure 16-1: Composition of blood
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Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Hematopoiesis: Blood Cell Formation Hematopoiesis: Blood Cell Formation
• Mostly in bone marrow from stem cells
• Rate regulated by cytokines & growth
factors
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Hematopoiesis: Blood Cell Formation Hematopoiesis: Blood Cell Formation
Figure 16-3: Hematopoiesis
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Focus on RBCs:
Focus on RBCs:
• Lose their nucleus
• Cytoskeleton – shape
• Hemoglobin
• Binds O 2 in heme group
• Binds some CO 2 on globulin
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Focus on RBCs:
Focus on RBCs:
Figure 16-5c: Bone marrow
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Focus on RBCs:
Focus on RBCs:
Figure 16-7a, b: Bone marrow
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Iron Metabolism: Key to Hemoglobin O 2 Transport Iron Metabolism: Key to Hemoglobin O 2 Transport
Figure 16-8: Iron metabolism
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Some Diseases of RBCs and O 2 Transport Some Diseases of RBCs and O 2 Transport
Table 16-3: Causes of Anemia
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Blood Components: Platelets Blood Components: Platelets
Figure 16-10c: Megakaryocytes and platelets
• Coagulate, form plug, prevent blood loss
• Formed by fragmentation from
megakaryoctyes
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Overview of Hemostasis:
Clot Formation & Vessel Repair Overview of Hemostasis:
Clot Formation & Vessel Repair
Figure 16-11: Overview of hemostasis and tissue repair
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Hemostasis: Vasoconstriction & Plug Formation Hemostasis: Vasoconstriction & Plug Formation
• Vasoconstriction
• Platelet activation
• Multiple factors
• Positive feedback
• Aggregation
• Loose plug
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Hemostasis: Vasoconstriction & Plug Formation Hemostasis: Vasoconstriction & Plug Formation
Figure 16-12: Platelet plug formation
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24
Hemostasis involves the interaction of:
Hemostasis involves the interaction of:
• Vascular Endothelium
• Platelets
• Coagulation Factors and
• Fibrinolytic Proteins
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Hemostasis: Coagulation & Clot Stabilization Hemostasis: Coagulation & Clot Stabilization
Figure 16-13: The coagulation cascade
• Prothrombin
• Ca++
• Fibrinogen
• Fibrin
• Polymerization
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Hemostasis has 2 main functions:
1. Induce a rapid & localized hemostatic plug at the site of vascular injury (clot formation)
2. Maintain Blood in a fluid, clot-free
state after the injury is healed
(clot dissolution)
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Endothelium vs. subendothelium 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.
Endothelium
Subendothelium
Source: http://facstaff.gpc.edu/~jaliff/vein1.gif
Beginning Review Quiz
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Primary Hemostasis Primary Hemostasis
Injury
Endothelial Cells
Exposure of thrombogenic surface
(subendothelial extracellular matrix)
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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
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Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
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Secondary Hemostasis 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
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Hemostasis: Coagulation & Clot Stabilization Hemostasis: Coagulation & Clot Stabilization
Figure 16-13: The coagulation cascade
• Prothrombin
• Ca++
• Fibrinogen
• Fibrin
• Polymerization
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Clinical Significance of Intrinsic and Extrinsic Pathways 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 or medical devices.
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Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Platelet Inhibitors Platelet Inhibitors
• Irreversible Cycloxygenase inhibitors
• Aspirin
• Triflusal (Disgren)
• Adenosine diphosphate (ADP) receptor inhibitors
• Cangrelor (Kengreal)
• Clopidogrel (Plavix)
• Prasugrel (Effient)
• Ticagrelor (Brilinta)
• Ticlopidine (Ticlid)
• Phosphodiesterase inhibitors
• Cilostazol (Pletal)
• Protease-activated receptor-1 (PAR-1) Antagonists
• Vorapaxar (Zontivity)
• Glycoprotein IIB/IIIA inhibitors (intravenous use only)
• Abciximab (ReoPro)
• Eptifibatide (Integrilin)
• Tirofiban (Aggrastat)
• Adenosine reuptake inhibitors
• Dipyridamole (Persantine)
• Thromboxane inhibitors
• Thromboxane synthase inhibitors
• Thromboxane receptor antagonists
• Terutroban
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PT and aPTT testing 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
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Pharmacologic considerations 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 Review Quiz
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Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Overview of Traditional and Newer Antithrombotic Agents
Baron TH et al. N Engl J Med 2013;368:2113-2124.
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Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Dissolving the Clot and Anticoagulants Dissolving the Clot and Anticoagulants
• Bleeding stopped
• Vessel repair
• Plasmin
• Fibrinolysis
• Clot dissolved
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Dissolving the Clot and Anticoagulants Dissolving the Clot and Anticoagulants
Figure 16-14: Coagulation and fibrinolysis
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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
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Coagulation and Disease 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…)
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DIC (Disseminated Intravascular Coagulation) DIC (Disseminated Intravascular Coagulation)
Massive Injury or Sepsis
Massive release of Tissue Factor III Excessive Activation of Thrombin
Coagulation becomes systemic
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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
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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
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings