Qiang XIA (), PhDDepartment of PhysiologyRoom C518, Block C, Research Building, School of MedicineTel: 88208252Email: xiaqiang@zju.edu.cnBLOOD

Internal environment

HomeostasisHomeostasis (from the Greek words for same and steady):maintenance of static or constant conditions in the internal environmentWalter B. Cannonhttp://www.harvardsquarelibrary.org/unitarians/cannon_walter.html

Components of Homeostasis:Concentration of O2 and CO2 pH of the internal environment Concentration of nutrients and waste products Concentration of salt and other electrolytes Volume and pressure of extracellular fluid

----RegulationBody's systems operate together to maintain homeostasis:Skin systemSkeletal and muscular systemCirculatory systemRespiratory systemDigestive systemUrinary systemNervous systemEndocrine systemLymphatic systemReproductive systemHow is homeostasis achieved?

Components of bloodPlasmaBlood CellsRed Blood Cells (RBC) or ErythrocytesWhite Blood Cells (WBC) or LeucocytesPlatelets (PLT) or Thrombocytes

Plasma includes water, ions, proteins, nutrients, hormones, wastes, etc.

the volume of red blood cells as a percentage of centrifuged whole bloodM: 40~50%F: 37~48% Hematocritpacked cell volume,

International Council for Standardization in Haematology (ICSH) Recommendations for "Surrogate Reference" Method for the Packed Cell Volume

Physical & chemical properties of blood1. Specific GravityDepending on hematocrit & protein composition Whole blood1.050~1.060Plasma1.025~1.035Red blood cells1.090

2. Viscosity

relative viscosity of whole blood 4~5 depending on hematocritrelative viscosity of plasma 1.6~2.4 related to the protein composition of the plasma

3. Osmotic PressureThe osmotic pressure of a solution depends on the number of solute particles in the solution, NOT on their chemical composition and size

Plasma osmotic pressure (~300 mOsm/LCrystalloid Osmotic PressurePressure generated by all crystal substances, particularly electrolytesImportant in maintaining fluid balance across cell membranesColloid Osmotic PressureOsmotic pressure generated by plasma proteins, particularly albumin. Approximately 25 mmHg, but important in fluid transfer across capillaries

4. Plasma pHNormal range: 7.35~7.45Buffer systems:NaHCO3/H2CO3, Pro-Na/Pro, Na2HPO4/NaH2PO4Hb-K/Hb, HbO2-K/HbO2, K2HPO4/KH2PO4, KHCO3/H2CO3

Functions of bloodTransportation O2 and CO2 Nutrients (glucose, lipids, amino acids) Waste products (e.g., metabolites) Hormones RegulationpHBody temperatureProtectionBlood coagulationImmunity

Plasma

Water (92% of plasma)serves as transport medium; carries heat Proteins (6~8% of plasma)Inorganic constituents (1% of plasma) e.g., Na+, Cl-, K+, Ca2+Nutrients glucose, amino acids, lipids & vitamins Waste products e.g., nitrogenous wastes like urea Dissolved gases O2 & CO2 Hormones

Composition

Albumins (60-80% of plasma proteins) most important in maintenance of osmotic balance produced by liver Globulins (1-, 2-, -, -)important for transport of materials through the blood (e.g., thyroid hormone & iron) clotting factors produced by liver except -globulins which are immunoglobulins (antibodies) produced by lymphocytes Fibrinogen important in clotting produced by liver

Red blood cells (Erythrocytes)

StructureBiconcaveNo nucleusFew organellesSmallHemoglobin molecules

CountRBC countM: 4.0~5.51012/LF: 3.5~5.01012/LHemoglobinM: 120~160 g/LF: 110~150 g/L

Physiological properties Plastic deformability

Erythrocyte Sedimentation Rate (ESR)The distance that red blood cells settle in a tube of blood in one hourNormal value [Westergren method]:M: 0~15 mm/hF: 0~20 mm/hAn indication of inflammation which increases in many diseases, such as tuberculosis & rheumatoid arthritis Suspension stabilityInternational Council for Standardization in Haematology (ICSH)

rouleaux formation

Osmotic fragility the susceptibility of a red blood cell to break apart when exposed to saline solutions of a lower osmotic pressure than that of the human cellular fluid

Notice that hemolysis begins in the 0.45% tube and is complete in the 0.35% tube.

Function of RBCs 1. Transport of O2 and CO22. Buffering

White blood cells (Leucocytes)Types of WBC

WBC Count (109/L) %GranulocytesNeutrophils2.0~7.050~70Eosinophils0.02~0.50.5~5Basophils0~0.10~1Monocytes0.12~0.83~8Lymphocytes0.8~4.020~40Total 4~10WBC count

Platelets (Thrombocytes)Formed in the bone marrow from cells called megakaryocytes Without nucleus, but can secrete a variety of substances normal value: (100~300) x 109/LAverage lifespan=7~14 days Play an important role in hemostasis

1. AdhesionPlatelets adhere to the vessel wall at the site of injuryPhysiological properties of plateletsvon Willebrand factor, vWF

2. AggregationPlatelets adhere to one another

3. Release or secretion:

Platelets contain alpha and dense granulesDense granules: containing ADP or ATP, calcium, and serotonin -granules: containing platelet factor 4, PDGF, fibronectin, B-thromboglobulin, vWF, fibrinogen, and coagulation factors V and XIII

Schematic drawing of the platelet (top figure), showing its alpha and dense granules and canalicular system. The bottom figure illustrates the platelet's major functions, including secretion of stored products, as well as its attachment, via specific surface glycoproteins (GP), to denuded epithelium (bottom) and other platelets (left). VWF: von Willebrand factor; TSP: thrombospondin; PF4: platelet factor 4; PDGF: platelet derived growth factor; b-TG: beta thromboglobulin; ADP: adenosine diphosphate; ATP: adenosine triphosphate.

4. ContractionClot retraction ()

5. Adsorption Clotting factors: I, V, XI, XIII

Hemostasis The arrest of bleeding following injury and the result of 3 interacting, overlapping mechanisms:Vascular spasmFormation of a platelet plugBlood coagulation (clotting)

Bleeding time ()

Signaling mediates responses to damage in a blood vessel:

adjacent endothelial cells are a source of signals that influence platelet aggregation and alter blood flow and clot formation at the affected site.

Role of platelets in hemostasisRelease of vasoconstricting substances Formation of the "platelet plug" Promotion of blood clotting Clot retraction

Clotting factorsClotting factorSynonymsIfibrinogenII prothrombinIII tissue thromboplastinIV Ca2+VproaccelerinVII proconvertinVIIIantihemophilic factorIXplasma thromboplastin componentXStuart-Prower factorXI plasma thromboplastin antecedentXIIcontact factorXIII fibrin-stabilizing factorBlood coagulation

Coagulation factors and related substances

Number and/or nameFunctionI (fibrinogen)Forms clot (fibrin)II (prothrombin)Its active form (IIa) activates I, V, VII, VIII, XI, XIII, protein C, plateletsTissue factorCo-factor of VIIa (formerly known as factor III)CalciumRequired for coagulation factors to bind to phospholipid (formerly known as factor IV)V (proaccelerin, labile factor)Co-factor of X with which it forms the prothrombinase complexVIUnassigned old name of Factor VaVII (stable factor)Activates IX, XVIII (antihemophilic factor)Co-factor of IX with which it forms the tenase complexIX (Christmas factor)Activates X: forms tenase complex with factor VIIIX (Stuart-Prower factor)Activates II: forms prothrombinase complex with factor VXI (plasma thromboplastin antecedent)Activates IXXII (Hageman factor)Activates factor XI and prekallikreinXIII (fibrin-stabilizing factor)Crosslinks fibrinvon Willebrand factorBinds to VIII, mediates platelet adhesionprekallikreinActivates XII and prekallikrein; cleaves HMWKhigh-molecular-weight kininogen (HMWK)Supports reciprocal activation of XII, XI, and prekallikreinfibronectinMediates cell adhesionantithrombin IIIInhibits IIa, Xa, and other proteases;heparin cofactor IIInhibits IIa, cofactor for heparin and dermatan sulfate ("minor antithrombin")protein CInactivates Va and VIIIaprotein SCofactor for activated protein C (APC, inactive when bound to C4b-binding protein)protein ZMediates thrombin adhesion to phospholipids and stimulates degradation of factor X by ZPIProtein Z-related protease inhibitor (ZPI)Degrades factors X (in presence of protein Z) and XI (independently)plasminogenConverts to plasmin, lyses fibrin and other proteinsalpha 2-antiplasminInhibits plasmintissue plasminogen activator (tPA)Activates plasminogenurokinaseActivates plasminogenplasminogen activator inhibitor-1 (PAI1)Inactivates tPA & urokinase (endothelial PAI)plasminogen activator inhibitor-2 (PAI2)Inactivates tPA & urokinase (placental PAI)cancer procoagulantPathological factor X activator linked to thrombosis in cancer

Exploration of the details of the clotting pathway has yielded detailed information about the sequence, only a portion of which is represented here. Note thrombins influence in three different directions.

Coagulation cascade3 processes2 pathways

A deficiency of a clotting factor can lead to uncontrolled bleeding. Vitamin K is a cofactor needed for the synthesis of factors II, VII, IX, & X in the liver. So a deficiency of Vitamin K predisposes to bleeding.

Serum serum = plasma fibrinogen and some of the other clotting factors + substances released by vascular endothelial cells andplateletsClotting time ()4-12 min

Which of the following statements is correct? A Damaged tissue releases a substance called tissue fibrinogen, which is mainly composed of phospholipids B Damage to the vessel wall initiates what is called the intrinsic pathway C The activation of protein coagulation factor plus the release of platelet thromboplastin eventually leads directly to the formation of thrombin D The actual blood clotting is caused by a conversion of the plasma protein prothrombin into another protein thrombin, which is the enzyme that causes the polymerization of the plasma fibrinogen molecules into fibrin threads that lead to blood clotting E Damage to platelets causes the release of platelet thromboplastin, which has an effect similar to tissue prothrombin

Which of the following statements is correct? A Damaged tissue releases a substance called tissue fibrinogen, which is mainly composed of phospholipids B Damage to the vessel wall initiates what is called the intrinsic pathway C The activation of protein coagulation factor plus the release of platelet thromboplastin eventually leads directly to the formation of thrombin D The actual blood clotting is caused by a conversion of the plasma protein prothrombin into another protein thrombin, which is the enzyme that causes the polymerization of the plasma fibrinogen molecules into fibrin threads that lead to blood clotting E Damage to platelets causes the release of platelet thromboplastin, which has an effect similar to tissue prothrombin

Which of the following substances enzymatically causes the polymerization of plasma fibrinogen? A Thromboplastin B Prothrombin C Prothrombin Activator D Thrombin E Phospholipids

Which of the following substances enzymatically causes the polymerization of plasma fibrinogen? A Thromboplastin B Prothrombin C Prothrombin Activator D Thrombin E Phospholipids

Serine Protease InhibitorAntithrombin IIIIIIinhibiting all serine proteases of the blood coagulation system, including: thrombin factor IXa, Xa, XIa, XIIaAnticoagulants

Protein C systemCProtein C, thrombomodulin, Protein S

Tissue factor pathway inhibitor (TFPI)

In an uninjured vessel,thrombin bound to thrombomodulin activatesprotein C, which blocks theclotting response.

HeparinA polysaccharide produced by the tissue mast cells and the basophils of circulating bloodInterfering primarily with the action of thrombin after combining with antithrombin III

Fibrinolysis2 processesActivation of plasminogenDegradation of fibrin4 components of plasma fibrinolysis systemPlasminogenPlasminPlasminogen activatorPlasminogen inhibitor

Following tissue repair, fibrin clots are dissolved in a process mediated by plasmin; synthetic plasminogenactivators can be used immediately after a stroke orheart attack to help dissolve clots and restore blood flow.

2 pathways of plasminogen activationFibrin Degradation Products (FDP)

Thank you for your attention!

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