1. Physiology of blood system.

2. Blood system Blood system firstly was proposed by Lung in 1936.
It consist of
- blood circulated through the blood circulatory system
- blood forming organs
- blood destroying organs
- regulatory apparatus.

3. Functions of blood Transport of cells and compounds
Limit blood loss through damaged vessels
Defend against pathogens, toxins

4. Amount of blood
The amount of blood in the body has been measured in various ways.
Naturally the volume of blood can be expected to vary with the size of the body.
The blood volume of an adult human of average size is about 6-8 %
in man – mL/kg;
woman – mL/kg.

5. Blood Components Plasma (55%)
water (90%), ions, proteins, gases, nutrients, wastes, hormones
Cells (45%)
RBCs, WBCs, platelets
Develop from stem cells in bone marrow

6. Plasma Water – 90 % Solids – 10 % Proteins – 8 % Others – 1,1 %
sodium,
calcium,
potassium,
magnesium,
chloride,
bicarbonate,
phosphate,
sulfate
Proteins – 8 %
serum albumin,
serum globulin,
fibrinogen
Others – 1,1 %
Nonprotein nitrogenous substances:
urea,
uric acid,
creatine,
creatinine,
ammonium salts,
amino acids
Nonnitrogenous substances:
glucose,
fats,
cholesterol hormones
Water – 90 %
Solids – 10 %
Inorganic chemicals – 0,9 %
Organic chemicals – 9,1 %
Gases
oxygen,
carbon dioxide,
nitrogen

7. Proteins One liter of plasma has 65-85 gram of proteins.
Concentration of
albumins is g/L;
globulins is
alpha-1-globulins – 1-4 g/L,
alpha-2-globulins – 4-8 g/L,
beta-globulins – 6-12 g/L,
gamma-globulins – 8-16 g/L;
fibrinogen – 2-4 g/L.
Plasma which are not contain fibrinogen called serum (it is necessary for understanding the immunology, therapy etc.)

8. Albumins
Albumins: on 80 % it provides oncotic pressure, contacts with bilirubin, fat acids, antibiotics, sulfanilamides.
It connects with them and transports them.
It produces in liver in average quantity of 17 gram per day.

9. Globulins Globulins produces in average quantity of 5 gram per day.
in lymphatic nodes,
in liver,
in bone marrow
Alpha-1-globulins connected with carbohydrates This is glycoproteins.
(for example 2/3 of all glucose connected with alpha-1-globulins)
Alpha-2-globulins connect 90 % of cupper. This is cerruloplasmin.
Its may produced in hormones, for example, thyroxin, connected by vitamin B12.
From this protein produce angiotensins (substances which are take place in increase of blood pressure).
Beta-globulin carry out 75 % of fats, iron (for example, transferrin).
Gamma-globulins has protective functions (for example, antibodies).
two-thirds

10. Fibrinogen
Fibrinogen is a protein which are produced by liver and take place in hemostasis system.
Fibrinogen is dissolved form, which transform in insolved form – fibrin and provide coagulative hemostasis (plug production) and prevent bleeding.
Daily production of fibrinogen is 2-4 g/L.

12. Quantity of cells, their changing
Erythrocytes (In men – 4,0-5,1 Tera/L; in women – 3,7-4,7 Tera/L. )
The quantity of erythrocytes may be increase – in pregnancy, in physical training, mental work, in newborn or decrease.
Leukocytes (Their number is 4-9 Giga/L. )
The number of leukocytes may increase – physical work, emotional load, in newborn, inflammation or decrease.
Platelets (Their number is Giga/L.)

13. Occurs in red bone marrow
Blood Cell Formation
Hematopoiesis: blood cell formation
Hemopoiesis—The cellular pathways by which the formed elements are produced.
Stem cells (hemocytoblasts)—Cells that divide and mature to produce all three classes of formed elements.
skull,
pelvis,
ribs, s
ternum,
humerus,
femur
Occurs in red bone marrow

14. What are Red Blood Cells?
Also called, erythrocytes or RBCs
Make up about 45% of whole blood volume
Make up 99.9% of the formed elements
Red blood cells (RBCs) are the most numerous cells in the body.
They circulate for about four months before being recycled; millions are produced each second.

15. Hematocrit—Percentage of whole blood volume taken up by formed elements (mostly RBCs). In clinical shorthand, it’s called, the “crit.”

16. What are the Properties of RBCs?
Transport oxygen and carbon dioxide in blood stream
Lack most organelles
Makes more room for hemoglobin
Degenerate after about 120 days
The hemoglobin inside transports oxygen from the lungs to peripheral tissues and carbon dioxide from the tissues to the lungs.

17. The Anatomy of Red Blood Cells

18. What is the Red Blood Cell Composition?
Hemoglobin makes up 95% of RBC protein
Globular protein composed of four subunits
Each subunit contains:
A globin protein chain
A molecule of heme
An atom of iron
A binding site for one oxygen molecule

19. What are White Blood Cells (WBCs)?
Also called, leukocytes
Defend the body against:
Pathogens
Toxins
Abnormal cells
Damaged cells

20. What are the Three Types of Granulocytes?
Neutrophils
50–70% of circulating WBCs
Phagocytic
Eosinophils
Less common
Attracted to foreign proteins
Basophils
Release histamine
Promote inflammation

21. What are Two Types of Agranulocytes?
Lymphocytes
Found mostly in lymphatic system
Provide specific defenses
Attack foreign cells
Produce antibodies
Destroy abnormal (cancer) cells
Monocytes
Migrate into tissues
Become macrophages
Live as phagocytic amoeba

22. Platelets Produced in the bone marrow
Cell fragments (irregularly- shaped bodies)
Needed for clotting blood

23. HEMOSTASIS Hemostasis
The process by which the body stops bleeding upon injury and maintains blood in the fluid state in the vascular compartment
Process is rapid and localized

24. HEMOSTASIS The primary players in hemostasis include Blood vessels
Platelets
Plasma proteins
Coagulation proteins – involved in clot formation
Fibrinolysis – involved in clot dissolution
Serine protease inhibitors
Other minor players include
Kinin system
Complement system

25. HEMOSTASIS
Defects
In blood vessels, platelets or serum proteins can be corrected by utilization of the other 2 players
In 2 of the 3 players results in pathologic bleeding
Blood Vessels
Plasma Proteins
Platlets

26. HEMOSTASIS Hemostasis can be divided into two stages
Primary hemostasis
Response to vascular injury
Formation of the “platelet plug” adhering to the endothelial wall
Limits bleeding immediately
Secondary Hemostasis
Results in formation of a stable clot
Involves the enzymatic activation of coagulation proteins that function to produce fibrin as a reinforcement of the platelet plug
Gradually the stable plug will be dissolved by fibrinolysis

27. FORMATION OF A STABLE PLUG

28. VASCULAR SYSTEM
Smooth and continuous endothelial lining is designed to facilitate blood flow
Intact endothelial cells inhibit platelet adherence and blood coagulation
Injury to endothelial cells promotes localized clot formation
Vasoconstriction
Narrows the lumen of the vessel to minimize the loss of blood
Brings the hemostatic components of the blood (platelets and plasma proteins) into closer proximity to the vessel wall
Enhances contact activation of platelets
Von Willebrand factor
Collagen fibers
Platelet membrane glycoprotein Ib
Activated platelets enhance activation of coagulation proteins

29. PRIMARY HEMOSTASIS Platelets Interact with injured vessel wall
Interact with each other
Produce the primary hemostatic plug
Primary platelet plug
Fragile
Can easily be dislodged from the vessel wall

30. PLATELETS Platelets Small, anucleated cytoplasmic fragments
Released from megakaryocytes in the BM
Megakaryocyte proliferation is stimulated by thrombopoietin (TPO)
Humoral factor
Produced primarily by liver, kidney, spleen, BM
Produced at a relatively constant rate
Normal platelet count is x 109/L
Survive 9-12 days
Nonviable or aged platelets removed by spleen & liver
2/3 of platelets circulate in the peripheral blood
1/3 are sequestered in the spleen
These 2 pools are in equilibrium and constantly exchanging
Spontaneous hemorrhaging occurs when platelet count gets below 10 x 109/L

31. PLATLETS

32. MATURE MEGAKARYOCYTE

33. PLATELET RELEASE

34. PLATELET FUNCTION Platelets function to
Provide negatively charged surface for factor X and prothrombin activation
Release substances that mediate vasoconstriction, platelet aggregation, coagulation, and vascular repair
Provide surface membrane proteins to attach to other platelets, bind collagen, and subendothelium

35. PLATELETS Are the primary defense against bleeding
Circulate in resting state
Have minimal interaction with other blood components or the vessel wall
Morphology of resting platelet is smooth, discoid
When stimulated by endothelial damage, platelets become activated and they
Become round and ‘sticky’
Build a hemostatic plug
Provide reaction surface for proteins that make fibrin
Aid in wound healing
Platelet activation and plug formation involves
Adhesion
Shape change
Secretion
Aggregation

36. ADHESION
Damage to endothelium exposes blood to the subepithelial tissue matrix with adhesive molecules
Platelet receptor GPIb binds to subendothelium collagen fibers through von Willebrand’s factor (vWF)
Platelet adherence stops the initial bleeding

37. SHAPE CHANGE
Following vessel injury and platelet exposure to external stimuli, platelets change their shape from circulating discs to spheres with pseudopods
Shape change is mediated by an increase in cytosolic calcium
Exposure of platelet membrane phospholipids promotes the assembly of vitamin-K dependent factors on the platelet membrane surface
Activated platelets adhere to exposed collagen

38. CHANGE IN PLATELET SHAPE

39. AGGREGATION Platelet-to-platelet interaction
Begins seconds after vascular injury and platelet adhesion
Requires dense granule release from the adhering platelets
Requires Ca++ and ATP
Requires fibrinogen and fibrinogen receptors GPIIb and IIIa
Mechanism:
ADP released from platelet cytoplasm upon adherence induces exposure of fibrinogen receptors GPIIb and IIIa
Fibrinogen binds to the exposed GPIIb and IIIa
Extracellular Ca++-dependent fibrinogen bridges form between adjacent platelets, thereby promoting platelet aggregation
This is primary or reversible aggregation
Secondary aggregation begins with the release of dense granules
Secondary aggregation is considered irreversible

40. SECRETION
Secondary aggregation begins with platelet secretion of dense granules
Dense granules contain large amounts of ADP
ADP binds to the platelet membrane triggering the synthesis and release of TXA2
The release of large amounts of ADP combined with TXA2 amplifies the initial aggregation of platelets into a large platelet mass

41. FORMATION OF PRIMARY HEMOSTATIC PLUG

42. PLATELETS AND SECONDARY HEMOSTASIS
Primary platelet plug is
Unstable and easily dislodged
Secondary hemostasis
Fibrin formation stabilizes the platelet plug
Proteins interact to form fibrin assemble on negatively charged membrane phospholipids of activated platelets

43. Coagulation
A set of reactions in which blood is transformed from a liquid to a gel
Coagulation follows intrinsic and extrinsic pathways
The final three steps of this series of reactions are:
Prothrombin activator is formed
Prothrombin is converted into thrombin
Thrombin catalyzes the joining of fibrinogen into a fibrin mesh

44. Coagulation

45. Detailed Events of Coagulation

46. Coagulation Phase 1: Two Pathways to Prothrombin Activator
May be initiated by either the intrinsic or extrinsic pathway
Triggered by tissue-damaging events
Involves a series of procoagulants
Each pathway cascades toward factor X
Once factor X has been activated, it complexes with calcium ions, PF3, and factor V to form prothrombin activator

47. Coagulation Phase 2: Pathway to Thrombin
Prothrombin activator catalyzes the transformation of prothrombin to the active enzyme thrombin

48. Coagulation Phase 3: Common Pathways to the Fibrin Mesh
Thrombin catalyzes the polymerization of fibrinogen into fibrin
Insoluble fibrin strands form the structural basis of a clot
Fibrin causes plasma to become a gel-like trap
Fibrin in the presence of calcium ions activates factor XIII that:
Cross-links fibrin
Strengthens and stabilizes the clot

49. Fibrinogen
Fibrin

50. Thrombin
Fibrinogen
Fibrin

51. Prothrombin Xa Va
Thrombin
Fibrinogen
Fibrin

52. Extrinsic Pathway TF
Prothrombin
VIIa Xa Va
Thrombin
Fibrinogen
Fibrin

53. Intrinsic pathway
XIIa
Extrinsic Pathway
XIa TF
Prothrombin
IXa
VIIa
VIIIa Xa Va
Thrombin
Fibrinogen
Fibrin

54. Intrinsic pathway XIIa Extrinsic Pathway XIa TF Prothrombin IXa VIIa
VIIIa Xa Va
Soft clot
Thrombin
Fibrinogen
Fibrin
XIIIa
Hard clot
Fibrin

55. Intrinsic pathway XIIa Extrinsic Pathway XIa TF Prothrombin IXa VIIa
VIII
VIIIa Xa Va V
Soft clot
Thrombin
Fibrinogen
Fibrin
XIIIa
Hard clot
Fibrin

56. The intrinsic pathway begins with the contact factors, factor XII, HMWK, and prekallikrein, which activates factor XI.
Activated factor XI can then activate factor IX, which then acts with its cofactor, factor VIII, to form tenase complex on a phospholipid surface to activate factor X.
Activated factor X then combines with its cofactor, factor V, to form the prothrombinase complex on a phospholipid surface, converting prothrombin to thrombin.

57. (Tissue Factor Pathway)
Extrinsic pathway
(Tissue Factor Pathway) IX TF
Prothrombin (II)
IXa
VIIa Xa
Thrombin (IIa)
NB: production of IXa
Interaction of intrinsic and extrinsic pathways

58. Tissue Factor Pathway Inhibitor
Kunitz-type protease inhibitor (kringles)
34 and 41 kD forms in plasma (C-term truncation)
Directly inhibits Xa
Inhibits VIIa-TF complex in a [Xa]-dependent manner
Bound to LDL, HDL and Lp (a)
~10% present in platelets (endothelium also)

59. Tissue Factor Pathway InhibitorIX TF
Prothrombin (II)
IXa
VIIa Xa
TFPI
TFI
Thrombin (IIa)
NB: Inhibition of Xa and VIIa

60. Net result: Tissue Factor Pathway Production of IXa
Production of small amounts of
thrombin (IIa)
NB: no/little fibrin formed!

61. Tissue Factor Pathway VIIa forms as usual via binding of VII to TF
VIIa activates some XXa
Xa converts a small amt of prothrombin to thrombin; this thrombin is used to produce small amts of VIIIa and Va
As the conc of TF-VIIa-Xa-thrombin increases, Tissue Factor Pathway Inhibitor inactivates this complex stopping further production of thrombin.
New: VIIa also activates IXIXa (Key to new scheme)
IXa, with VIIIa (produced as above), produces Xa; this Xa with Va (produced as above) produces new thrombin; this thrombin produces more VIIIa and Va and now we get lots of thrombin and fibrin!

62. V
VIII
Thrombin (IIa) Va
VIIIa

63. Tissue Factor Pathway NB: activation of IX by VIIa IX TF Prothrombin
IXa
VIIa
VIII
VIIIa Xa Va V
Soft clot
Thrombin
Fibrinogen
Fibrin
XIIIa
Hard clot
Fibrin

64. Coagulative (secondary) hemostasis.
Characteristics of clotting factors
There are 12 clotting factors:
I – fibrinogen;
II – prothrombine;
III – thromboplastin of tissue;
IV – ions of calcium;
V – proaccelerin;
VII – proconvertin;
VIII – antihemophylic factor A;
IX – Christmas factor or antihemofilic factor B;
X – Stuart-Prower factor or prothrombinase;
XI – plasma thromboplastin antecedent;
XII – Hageman factor;
XIII – fibrin stabilizing factor.
Coagulative (secondary) hemostasis.

65. Anticoagulative mechanisms. Fibrinolysis.
The tendency of blood to clot is balanced by a number of limiting reactions that tend to prevent clotting inside the blood vessels and to break down any clots that do form.

66. The primary anticoagulants are antithrombin III heparin
(It is the most important anticoagulant in the blood);
heparin
(This substance was originally found in the liver, by large basophilic cells (mast cells) in tissues of various organs.
Heparin reduces the ability of the blood to clot by blocking the change of prothrombin to thrombin.
It can also be used to aid in reducing clots in cases in which internal clotting has already occurred.
Heparin form complex with antithrombin-III.
Activate nonenzyme fibrinolysis.);

67. alpha-2-macroglobulin,
Alpha-2-macroglobulin is a similar to antithrombin-heparin cofactor in that it combines with the proteolytic coagulation factors. Its activity is not accelerated by heparin. Its function is mainly to act as a binding agent for the coagulation factors and prevent their proteolytic action until they can be destroyed in various ways. It a faint inhibitor of thrombin, connect with plasmin.
alpha-1-antitripsin,
Alpha-1-antitripsin inhibits thrombin activity, IXa, XIa, XIIa factors, plasmin and kallilrein.
protein C
Protein C inhibits VIIIa, Va factors. Its activity depends on thrombin and vitamin K concentration.

68. Functioning of secondary anticlotting substances
Primary anticoagulants are produced and present all time in plasma and secondary anticoagulants form in a case of blood clotting.
They are antithrombin-I or fibrin and products of fibrinolysis or products of fibrinogen degradation.
Fibrin sorbs and inactivates thrombin and Xa factor.
Products of fibrinolysis inactivate ending stage of clotting, IXa factor, platelets' agregation.

69. Thank you for your attention!