(L21) The composition and features of blood

The heart’s primary function is to…

distribute oxygenated blood to tissue

Average adult’s blood volume is

~5L, 14,000L circulates every 24 hours

Large vessels…

close to the heart - high volume/low flow

Small capillaries…

in tissue - low volume/high flow

Thick muscular arteries…

carry blood away from the heart, provides constant back-pressure on the heart, ensures even flow of blood through tissue

Thinner walled veins…

Returns blood to heart, low pressure, so valves prevent back flow

Why do we need oxygen?

Respiration coupled to oxidative phosphorylation

O2 is the final electron acceptor in the mitochondrial electron transport chain used to make high energy ATP that powers most cell processes

Average blood pressure

120/80

• This is the pressure required to raise a column of mercury 120mm

120

(systole)

• max arteriole pressure when LV contracts

80

(diastole)

• min arterial pressure when the heart is in between beats

Hypotension

(too low)

• blood does not flow through capillaries

• low O2, high CO2 — weak, dizzy, tired

Hypertension

(too high)

• capillary rupture bleeding

• Abnormal clotting and stroke

Breathing is regulated via…

Sympathetic/parasympathetic nervous system sensing O2/CO2 levels in the blood

Oxygen/carbon dioxide exchange in the lung

1. Lung provides a _______ for efficient exchange of O2 and CO2

2. ________ (bright red) is carried _____ the lungs to the tissue by ________

3. _______ replaces ______ in the tissue

4. _________ (dark red) is carried back to the lungs

5. O2 replaces CO2 in the lung

Vast surface, oxyhaemoglobin, from, arteries, CO2, O2, carbaminohaemoglobin

Haem

Ring shaped iron containing a molecular component of haemoglobin needed to bind oxygen in the blood stream

Haemoglobin

Protein containing iron facilitating oxygen transport in red blood cells

The association and dissociation of O2 from haem is dependant on…

the partial pressure of O2

O2 readily associates in…

the lungs and dissociates in the tissues.

• CO2 is vice versa (associates in tissue, dissociates in lungs)

Other molecules readily ______ O2 from haem e.g. _____ (cherry red) and _______ (pinkish)

displace, cyanide, carbon monoxide

Air

pO2: 160

pCO2: 0.3

Lung alveoli

pO2: 100

pCO2: 35

Arterial blood

pO2: 80-100

pCO2: 40

Venous blood

pO2: 20-40

pCO2: 50

Major components of blood

1. Cells

2. Proteins

3. Lipids

4. Electrolytes

5. Vitamins, hormones

6. Glucose

Cell all originate in the ______ from a ________

Bone marrow, single stem cell

• Needed to identify cells

Cell types

1. Erythroid

2. Myeloid

3. Lymphoid

4. Platelets

Erythroid

Carries oxygen via the major protein haemoglobin

Myeloid

White cells provide innate immunity

Are the most abundant cell type

Lymphoid

White cells provide adaptive immunity

Platelets

Blood clotting and tissue repair

Proteins

1. Albumin

2. Haemoglobin

3. Fibrinogen

4. Immunoglobins

5. Hundreds more proteins at much lower amounts

Albumin

Constitutes nearly 50% of total protein in blood. Prevents changes in pH and osmolarity

Haemoglobin

In red blood cells. Contains iron. Binds and transports oxygen and carbon dioxide.

Fibrinogen

Essential for coagulation

Immunoglobulins

Antibodies provide highly specific immunity

Lipids

Bound in lipoproteins. High, low, and very low density — HDL (good), LDL (bad), VLDL

Electrolytes

Salts and minerals (HCO3-, Na+, Cl-, Ca++, Mg++, K+, creatine, creatinine

Vitamins, hormones

Needed for communication between tissue

Glucose

Primary energy source for glycolysis and the Krebs cycle

Plasma

• 55% of blood

• Fluid separated from cells

Buffy coat, composed of…

White blood cells and platelets

Red blood cells

• 45% of blood

• Protein + cells, protein level tested for compounds

Abundance of three main cell types

1. Erythrocytes

2. Leukocytes

3. Platelets

Erythrocytes

• Oxygen transport

• ~5-6 million/ml

Leukocytes

• Immune defence

• ~10,000/ml

Platelets

• Coagulation and tissue repair

• ~400,000/ml

Types of leukocytes

• Monocyte

• Eosinophil

• Basophil

• Neutrophil

• Lymphocytes

Innate immunity

Become macrophages (phagocytic)

• Monocyte

Neutrophil is most abundant (phagocytic)

• Eosinophil

• Basophil

• Neutrophil

Adaptive immunity

Antibodies and cellular immunity

• B and T cells

CD34+ stem cells represent 1 in 10,000 _____ in the ______. Small number can _______ people who have had ablation therapy for ________.

White blood cells, bone marrow, repopulate, leukaemia

• Single multi potent CD34+ stem cell gives rise to two paths of haemopoietic cells

Myeloid stem cells gives rise to…

Myelolasts that give rise to to

• Eosinophil

• Basophil

• Neutrophil

• Monocyte

(innate)

Lymphoid stem cells give rise to…

Lymphoblasts that give rise to:

Small lymphocytes — T (thymus gland) and B (blood) lymphocytes

(adaptive)

Every cell development stage is characterised by a unique set of…

Cell surface molecules

Monoclonal antibodies (mAb) are powerful ______ that can selectively ______ a ______ molecule like CD4

Reagents, bind, specific

Panels of fluorescent or magnetic mAbs are used to _________. Used diagnostically to quickly determine if you have a _________ e.g. _______ (low CD4 count) or _________ (very high leukocyte count).

Immunophenotype, blood disease, AIDS, leukaemia

CD stands for “_________” an international protocol that defines individual _________ markers of __________. There are now hundreds of CD ________ defined by mAbs used for ________. CD34+ essentially means a cell that _______ (is positive) the _________.

Cluster of differentiation, cell surface, cell differentiation, antigens, immunophenotyping, binds, anti-CD34+ mAbs

Immunophenotyping is…

a powerful tool to quantify and isolate individual cell populations from complex mixtures using mAb reagents

• Immunomagnetic cell sorting (MACS)

• Fluorescence-activated cell sorting (FACS)

Coagulation is…

the cleavage of fibrinogen to fibrin

Plasma

The viscous liquid fraction after centrifugation of cells. Requires an anti-coagulant such as heparin. Plasma still contains fibrinogen.

Serum

Clear viscous yellow liquid remaining after coagulation and separation of the fibrin clot and trapped cells on the bottom

Two main activation pathways

1. Intrinsic pathway (contact)

2. Extrinsic pathway (tissue damage)

Share common factor X

Intrinsic pathway

Contact

Factors XII, XI, IX, VIII

Extrinsic pathway

Tissue damage

Platelets, tissue factor, V, VII

Common factor X acts on…

Factor Xa — prothrombin to thrombin

Thrombin cleaves…

Fibrinogen into fibrin which crosslinks to form a clot

Plasminogen is concerted into active plans in to…

dissolve the fibrin clot resulting in degraded fibrin, process called thrombolysis

Tissue plasminogen activator (TPA)

Treatment for stroke, myocardial infarction (MI) and pulmonary embolism (PE) but must be administered early

Haemophilia is a serious genetic condition resulting in a defective ________. There are many forms of haemophilia and indeed many of the _______ were discovered from studying rare forms of haemophilia. The most common well-known and common is the ________ for _______ that was carried by Queen Victoria.

coagulation factor, factors, X-linked gene defect, VIII

Coagulation is a…

Proteolytic activation cascade

Many parasites and other microbes that rely on blood produce powerful anti-coagulants that typically target the…

thrombin step

complement

first line of defence against invading pathogens

A neutrophil senses _________ released by the bacterium. These _________ arise from _________ proteins that have coated the bacteria (called __________) and ________ neutrophils which then ________ (________) the bacterium

chemicals, chemicals, complement, opsonization, attract, engulf, phagocytose

Activation of complement proteins

• ____ major complement proteins attach to the ______ of the bacterium in a ______ cascade

• they form very ______ enzyme complexes called __________ on the bacterial surface that activate __________ more _________ that ultimately forms a ________ called the MAC.

• Complement ______ is the most abundant in blood

• 9, surface, proteolytic

• stable, convertases, successively, complement, lytic pore

• C3

Complement is a proteolytic activation cascade that is essential in…

innate immunity

Complement can be activated by three different pathways…

• Classical pathway

• Lectin pathway

• Alternate pathway

Classical pathway

mediated by antibodies IgM or IgG binding to a microbe surface which is then bound by complement C1

Lectin pathway

Involves complement components that recognise unique sugars on bacteria

Alternate pathway

Most important and involves direct activation of C3 when in close contact with the surface of a bacteria

Deposition of complement on microbes is essential for…

phagocytosis - called opsonisation

Deposited complexes are called

convertases - these activate more complement in an amplification loop (e.g. alternate)

Convertases are _________ bound through a ________ bond

irreversibly, covalent

Cleavage of C3, C4, and especially C5 produce ________ that are powerful _________ called ________ that attract and activate _________

The end stage of complement (________) forms a ________ that cause some bacteria to ______. This is the ____________

People with deficiencies in a ________ are susceptible to _______

complement component, chronic infections

Many microbes produce proteins called __________ that _________ the complement cascade

virulence factors, inhibit