1. Chapter 16
Blood

2. 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

3. Blood Components: Plasma Transports Solutes
Water, ions, trace elements
Gasses: O2 & CO2
Organic Molecules
Glucose
N–wastes
Proteins
Antibodies
Hormones

4. 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)

5. Blood Components: Plasma Transports Solutes
Figure 16-1: Composition of blood

7. Blood Components: "Blood Count" – % of Each Component
Figure 16-2: The blood count

8. Blood Components: Cells
Erythrocytes
Red Blood Cells (RBC)
O2 & CO2 transport
White Blood Cells (WBC)
Immune defense
Phagocytosis
Platelets: clotting

9. Blood Components: Cells
Figure 16-1: Composition of blood

11. Hematopoiesis: Blood Cell Formation
Mostly in bone marrow from stem cells
Rate regulated by cytokines & growth factors

12. Hematopoiesis: Blood Cell Formation
Figure 16-3: Hematopoiesis

13. Focus on RBCs: Lose their nucleus Cytoskeleton – shape Hemoglobin
Binds O2 in heme group
Binds some CO2 on globulin

14. Focus on RBCs:
Figure 16-5c: Bone marrow

15. Figure 16-7a, b: Bone marrow
Focus on RBCs:
Figure 16-7a, b: Bone marrow

16. Iron Metabolism: Key to Hemoglobin O2 Transport
Figure 16-8: Iron metabolism

17. Some Diseases of RBCs and O2 Transport
Table 16-3: Causes of Anemia

18. Blood Components: Platelets
Coagulate, form plug, prevent blood loss
Formed by fragmentation from megakaryoctyes
Figure 16-10c: Megakaryocytes and platelets

19. Overview of Hemostasis: Clot Formation & Vessel Repair
Figure 16-11: Overview of hemostasis and tissue repair

20. Hemostasis: Vasoconstriction & Plug Formation
Platelet activation
Multiple factors
Positive feedback
Aggregation
Loose plug

21. Hemostasis: Vasoconstriction & Plug Formation
Figure 16-12: Platelet plug formation

22. Hemostasis involves the interaction of:
Vascular Endothelium
Platelets
Coagulation Factors and
Fibrinolytic Proteins

23. Hemostasis: Coagulation & Clot Stabilization
Prothrombin
Ca++
Fibrinogen
Fibrin
Polymerization
Figure 16-13: The coagulation cascade

24. 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)

25. 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 Review Quiz

26. Primary Hemostasis Injury Endothelial Cells
Exposure of thrombogenic surface
(subendothelial extracellular matrix)

27. 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

29. 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

30. Hemostasis: Coagulation & Clot Stabilization
Prothrombin
Ca++
Fibrinogen
Fibrin
Polymerization
Figure 16-13: The coagulation cascade

31. 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.

34. 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

35. 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

36. 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

39. Overview of Traditional and Newer Antithrombotic Agents
Baron TH et al. N Engl J Med 2013;368:

47. Dissolving the Clot and Anticoagulants
Bleeding stopped
Vessel repair
Plasmin
Fibrinolysis
Clot dissolved

48. Dissolving the Clot and Anticoagulants
Figure 16-14: Coagulation and fibrinolysis

49. 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

50. 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…)

52. 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)

53. 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

54. 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

56. Summary
Blood is about 50% plasma, water solvent & solutes: ions, elements, gases, 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