Cardiovascular Physiology Lecture Outline

• General Functions
• Components
Part • Production & Function of Formed Elements
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• RBC specialized functionality
– Anemia
• Hemostasis
– Platelets & Coagulation

General Functions Gases

Nutrients Components
Chemical
messengers
• Functions as: Heat • Whole blood is divided into
Wastes
– a transport medium – Formed elements (45%) Neutrophils
• Erythrocytes Eosinophils
– a protective medium Platelet activation • Leukocytes
Basophils
Coagulation Lymphocytes
– a regulatory medium Adaptive Immunity • Thrombocytes Monocytes
Non-specific defenses – Plasma (55%)
– a hydraulic medium
• Extracellular matrix composed of
– Water Amino acids Albumins
pH – Ions Proteins Globulins
Temperature Glucose fibrinogens
– Organic molecules
Volume/Cell Count Lipids
Movement of tissues – Trace elements and vitamins Nitrogenous
Filtration force – gases CO2 wastes
O2

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Production & Function of Blood Cells Production & Function of Blood Cells
• Production of blood cells is called hematopoiesis • All blood cells differentiate from a
– Is initiated by week three of embryonic development
– Rate is influenced by cytokines pluripotent stem cell
• EPO (erythropoietin) – The Hematopoietic stem cell is
– Produced in the kidney
– Targets bone marrow & increases production of erythrocytes • Pluripotent because it is already partially
• TPO (thrombopoietin) differentiated… won’t produce anything else but
– Produced in the liver
– Targets bone marrow & increases production of
blood cell types
megakaryocytes
• CSFs, IL’s, SCF (stem cell factor)
– This process occurs in bone marrow
– Produced by the endothelium and fibroblasts of bone marrow • Mainly in the epiphyses (ends) of long bones and
and by leukocytes
– targets all blood cell types & increases activity of hematopoietic
in the flat bones (sternum, ribs, ilium)
stem cells

Production & Function of Blood Cells

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Production & Function of Blood Cells Production & Function of Blood Cells

• Red Blood Cell Production • Blood Cell Levels

– Low O2 levels initiate synthesis of hypoxia-inducible
factor-1 (HIF-1)
– HIF-1 turns on EPO gene and synthesis of EPO is on!
– Turns off as hypoxia is corrected due to the increase
in O2 carrying RBCs.

– Today EPO is produced by recombinant DNA

technology and other CSFs for WBCs
• Benefits?
– Cancer patients and
– athletes! (illegally)

Production & Function of Blood Cells RBC Specialized Function

• Colony-Stimulating Factors (CSFs) • Red Blood Cells

– Regulate wbc production and development = – Specialized aspects:
leukopoiesis • Biconcave shape
• Rate must be able to be quickly amped up as a – Approx 7um in diameter
mature leukocyte no longer undergoes mitosis – Due to cytoskeletal structure
– Any additional wbcs must come from stem cell activity – Aids in movement through capillaries and allows them to
maintain integrity even as osmotic pressures vary
• Production of a specific type is controllable by the
» Swelling vs. crenation (shrinking)
mature population of its type
– This ensures the correct leukocyte production for the
• Anucleate condition in mature rbcs
demand – Implications?
– Life span?

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 RBC Specialized Function RBC Specialized Function

• Red Blood Cells • Red Blood Cells

– Specialized aspects: – Hemoglobin (Hb)
• The last stage (immature form) of the production process is
called a reticulocyte • A quaternary protein (2 alpha & 2 beta units)
– Significant as a little bit of ER remains and is visible upon • Hb exhibits plasticity in its shape
microscopic evaluation – When O2 binding sites are fully loaded it is in its “tense”
» The ratio of reticulocytes to erythrocytes is used to monitor configuration
production rates
» Holds onto O2 with more tenacity
• Production and transport of hemoglobin (Hb) which accounts
for 97% of the content of a mature rbc! » Where does this happen?
– This comes to approximately 280 million hemoglobin – When O2 binding sites are less than fully loaded it enters
molecules/cell! a “relaxed” configuration
– Each Hb molecule carries 4 oxygen molecules » Makes binding and releasing O2 easier
– Increases the O2 carrying capacity of blood by about 70 times! » Where does this happen?

RBC Specialized Function RBC Specialized Function

Anemia
• Reduction in O2 carrying capacity in blood because of low Hb
• Red Blood Cells content.
• RBC damage and loss from
– Hemoglobin (Hb) production & iron conservation – Blood loss
Dietary Iron small % – Hemolytic anemia – cells bursting, may be
some lost lost in
Incorporated into RBCs circulate for • Hereditary such as
in sweat blood
hemoglobin in bone ~120 days “holding” – Sickle cell anemia
& urine
Intestinal Cells marrow by RBCs the iron in hemoglobin – Spherocytosis
• Aquired
– Parasitic issue – malaria, dengue fever
– Drugs
Transported in plasma
Excess iron – autoimmune issues
attached to the protein Old RBCs are
transferrin stored as ferritin phagocytosed in • Reduced capacity for RBC production
(Fe-transferrin) and hemosiderin liver and spleen – Aplastic anemia – cells don’t form correctly
– Loss/lack of iron (needed for Hb synthesis)
Biliverdin – Deficiency in folic acid (needed for DNA production)
converted to
bilirubin and – Deficiency of Vit B12 (needed for DNA production)
Heme is further Hb is broken down into
excreted in urine the heme and globin
• May be a result of lack of intrinsic factor – needed for B12 absorption
separated into Fe
and feces and biliverdin components – Low EPO production

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RBC Specialized Function Hemostasis
Polycythemia

• Too many RBCs (and WBCs too)
– May be due to stem cell dysfunction
– May be relative polycythemia
• The hematocrit is high but volume is normal
• Preventing blood loss occurs in a few steps
1. Vasoconstriction
– Reduces blood flow and pressure in damaged vessel
– Damage releases paracrines that cause immediate
constriction of smooth muscle

• Dehydration reduces plasma volume and therefore 2. Platelet Plug Formation

increases relative cell count. – The process of forming a physical plug to stop blood loss
3. Clot formation (coagulation cascade)
– Forms a clot (fibrin polymer)
– Why is polycythemia bad?

Hemostasis
Platelet Plug Formation

• Platelets stick to damaged vessel

– Release cytokines which initiate further
vasoconstriction and additional platelet
adhesion
– Sets up a cascading effect
– Leads to a loose plug being formed
• The damaged vessel at the same time
with collagen exposed and tissue factor
released starts the coagulation cascade

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Hemostasis Hemostasis
Coagulation
Coagulation Cascade
Cascade
• This coagulation forms a more
permanent clot!
• Two pathways to achieve this
– Intrinsic Pathway
• Exposed collagen activates the initiating factor of
the cascade event = factor XII
– Extrinsic Pathway
• Damaged tissues release tissue factor (factor III
or tissue thromboplastin)

Table of Factors involved with the
coagulation cascade
Number and/or name
I = fibrinogen
Table of other factors involved with
hemostasis
prekallikrein Activates XII and prekallikrein; cleaves HMWK
Function
Forms clot (fibrin) high-molecular-weight kininogen Supports reciprocal activation of XII, XI, and prekallikrein

II = prothrombin
III* = Tissue factor
IV* = Calcium
V = proaccelerin, labile factor
Its active form (IIa) activates I, V, VII, VIII, XI, XIII, protein C, fibronectin Mediates cell adhesion
platelets antithrombin III Inhibits IIa, Xa, and other proteases;
Co-factor of VIIa (formerly known as factor III) heparin cofactor II Inhibits IIa, cofactor for heparin and dermatan sulfate
Required for coagulation factors to bind to phospholipid (formerly
protein C Inactivates Va and VIIIa
known as factor IV)
Co-factor of X with which it forms the prothrombinase complex protein S Cofactor for activated protein C

VI
VII = stable factor
VIII = Anti Hemophilic factor A
IX = Anti Hemophilic Factor B or
Christmas factor
X = Stuart-Prower factor
XI = plasma thromboplastin
antecedent
XII = Hageman factor
XIII = fibrin-stabilizing factor
Unassigned – old name of Factor Va
protein Z
Name: Pro Convertin - Activates IX, X
Protein Z-related protease inhibitor
Co-factor of IX with which it forms the tenase complex
plasminogen
Activates X: forms tenase complex with factor VIII
alpha 2-antiplasmin
Activates II: forms prothrombinase complex with factor V tissue plasminogen activator (tPA)
urokinase
Activates IX
plasminogen activator inhibitor-1
Activates factor XI and prekallikrein
Crosslinks fibrin plasminogen activator inhibitor-2
cancer procoagulant
Mediates thrombin adhesion to phospholipids and stimulates
degradation of factor X by ZPI
Degrades factors X (in presence of protein Z) and XI
Converts to plasmin, lyses fibrin and other proteins
Inhibits plasmin
Activates plasminogen
Activates plasminogen
Inactivates tPA & urokinase (endothelial PAI)
Inactivates tPA & urokinase (placental PAI)
Pathological factor X activator linked to thrombosis in cancer

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Summary
• Blood as a transport, regulative, hydraulic
and protective medium
• Production of RBCs involves a recycling
aspect (Fe conservation)
• Hemostasis involves
– Vascular spasm
– Platelet plug formation
– Coagulation
– Functionally a postive feedback system