Blood Composition and Function

Blood Structure & Function Overview

• The aim is to describe the constituent elements of blood tissue, the structure and function of plasma, erythrocytes, leukocytes, and thrombocytes, and describe the 3 phases of haemostasis.
• Blood tissue includes plasma, erythrocytes (red blood cells), leukocytes (white blood cells), and thrombocytes (platelets).
  • Erythrocytes will cover anatomy & physiology, erythropoiesis, and blood groups.
  • Leukocytes will cover the 5 types: Neutrophils, Eosinophils, Basophils, Monocytes, and Lymphocytes in addition to immune response, haemopoiesis & stem cell lines.
  • Thrombocytes will cover haemostasis.

Function of Blood

• Blood has 3 main functions: transport, regulate, and protect.
• Blood transports oxygen from lungs to tissues, carbon dioxide from tissues to lungs, nutrients from digestive organs to cells, metabolic waste products from cells to kidneys, lungs and sweat glands, and hormones from endocrine glands to cells.
• Blood regulates body pH by acting as a buffer to prevent sudden changes in pH that could disrupt normal cell activities, absorbs & distributes heat throughout the body, and facilitates heat loss to the skin surface to regulate body temperature.
• Blood also regulates body water balance through a constant exchange of water between circulating blood and tissue fluid.
• Blood protects against infection through the actions of antibodies, complement proteins, and leukocytes (white blood cells). It also protects against blood loss through the actions of platelets & proteins if a blood vessel is damaged.

Blood Tissue

• Blood is a fluid, but it is also a tissue and a form of connective tissue. Tissue is a group of cells with a common purpose.
• Centrifugal force can separate different constituent substances of blood based on their density
• Typically, blood volume is ~55% plasma and ~45% "formed elements".
  • "Formed elements" include thrombocytes (blood platelets), leukocytes (white blood cells), and erythrocytes (red blood cells).
• Haematocrit defines the % of blood volume accounted for by RBCs.
  • Typical values are ~47% in males and ~42% in females.
• Leukocytes and platelets contribute <1% of blood volume.
• Plasma makes up most of the remaining bulk (~55%).

Plasma Composition

• Plasma is mostly water (~90%). The remaining consists of 10% solutes, with over 100 different sorts.
• Proteins (~7%) like Albumin which is produced by the liver, exerts osmotic pressure to maintain water balance between blood and tissue, Globulins including transport proteins & antibodies, and Clotting proteins like prothrombin and fibrinogen. Miscellaneous, such as hormones
• By-products of cellular metabolism (lactic acid, urea, etc.), organic nutrients like Glucose & other carbohydrates, Amino acids from proteins, Glycerol & triglycerides from fat, Cholesterol, and Vitamins.
• Electrolytes (sodium, potassium, calcium, etc.) and Gasses (oxygen, carbon dioxide) are some more components.

Erythrocytes

• Erythrocytes (red blood cells) are small, biconcave, anucleate discs specialized for transporting oxygen.
• Erythrocytes contain approximately 250 million molecules of haemoglobin per cell.
  • Globin is proteins containing 4 haems and Haem is ring of porphyrin around an iron-atom.
  • An oxygen molecule will readily bind to the iron (Fe) at the centre of each haem, i.e., up to 1 Bn oxygen molecules per erythrocyte
• The indented shape results in a very large surface area for rapid gas exchange.
• Erythrocytes are flexible, which is facilitated by a network of deformable proteins (e.g., "spectrin") attached to the inside of the plasma membrane, allow them to squeeze through tight capillaries.
• Oxygen is always close to the surface and No nucleus (or organelles) means more space for haemoglobin (& thus more oxygen) and also means none of the oxygen is consumed and "borrowed time” (100 – 120 days).
• There are about 5 million erythrocytes per mm3 of blood adding up to 20-30 trillion at any given time being ~70% of all cells by number.

Erythropoiesis

• Erythrocytes survive ~100-120 days.
  • Around 2.5x108 (250,000,000) cells are destroyed every day by the spleen.
• Erythropoiesis is the formation of new erythrocytes in the red bone marrow.
• Greek origins: erythro = red and poiesis = to make

The 5 stages of Erythropoiesis are:

• Commitment: A generic stem cell (haemocytoblast) commits to becoming a red blood cell (proerythroblast)
• Proliferation: the cell divides many times. This gives rise to basophilic erythroblasts that produce huge numbers of ribosomes
• Differentiation: Hemoglobin is synthesised and iron accumulates as the basophilic erythroblast transforms into a polychromatic erythroblast
• Maturation: Organelles ejected and its nucleus degenerates and is pinched off. This allows the cell to collapse inward and eventually assume the biconcave shape.
  • The result is the reticulocyte a young erythrocyte.
• from stem cell to reticulocyte takes around 15 days, the reticulocyte is then released into the blood and continues to mature for another ~2 days, at which point it is termed an erythrocytes.

Erythropoiesis Regulation

• It is important to maintain the right balance of red blood cells in the body because Too few erythrocytes leads to tissue hypoxia (oxygen deprivation) leading to necrosis and Too many makes the blood undesirably viscous.
• To ensure erythrocytes numbers remain within the homeostatic range, new cells are rapidly & continuously produced (2 million/second) with excess cells destroyed by the spleen.
• The regulation is controlled by oxygen-carrying capacity of the blood, triggering Erythropoietin (EPO) production in the kidney, stimulating red bone marrow.
• Failure to regulate erythropoiesis in Anemia happens in those suffering from Heart Failure, or Kidney disease (where uremic toxins accumulate and impact erythropoiesis)

Blood Groups

• "Immune response' is the bodies way of protecting itself against harmful pathogens.
  • It actually involves numerous separate responses, many of which involve WBCs (see later slides).
• A 'pathogen' is an ‘invading organism' that can cause disease.
  • An 'antigen' is something, for example on the surface of a pathogen, that is recognized by the body as 'foreign/harmful' or 'intrinsic/OK'.
  • An 'antibody' is produced by the body as part of its immune response to neutralise the antigen.
• Erythrocytes have many forms of antigens called "agglutinogens" on their surface, the unique combination of which determines your "blood group“.

4 ABO Blood Groups

• Up to 400 antigens determine a blood group on such antigens on RBCs, people can be categorised into 1 of 4 broad groups based on 2 antigens, referred to as "A" & “B”
  • Type A: Agglutinogen A
  • Type B: Agglutinogen B
  • Type AB: Agglutinogens A and B
  • Type O: Neither agglutinogen A nor B
• The plasma of a person carries the antibody (agglutinin) to the antigen they do not posses (i.e., will seek out and "agglutinate” the other type).
• Individuals with type AB blood have no antibodies, so they are 'universal recipients'.
• Type O blood is the 'universal donor' as it posses neither antigen.

Rhesus Blood Types

• First described in rhesus monkeys they rely on the presence of 6 antigens; C, D, E, c, d, e, however, Only C, D, and E cause immune reactions, so If an individual posses any of these antigens they are said to be Rh+, otherwise they are Rh-. Most people are Rh+
• The body does not usually contain the antibodies to these antigens, and they take several months to form. The wrong rhesus group can therefore be administered once (thereafter the antibodies are present).

Pregnancy & Jaundice

• If mother is Rh- & foetus is Rh+, problems can arise during pregnancy which is defined as rhesus incompatibility.
• As the foetal and maternal circulations are kept separated by the placenta, the mother will not produce antibodies 'against' her foetus
• However, during birth mixing of blood will occur and the mother will produce rhesus antibodies
• During a second pregnancy with a Rh+ foetus, the mother's antibodies will attack the foetus, destroying her baby's blood cells
• In such a case rhesus disease may occur where it doesn't harm the mother, but can cause the baby to become anaemic & develop jaundice

Leukocytes Overview

• Leukocytes do not have hemoglobin unlike Erythrocytes
• The are less numerous as approximately ~7000/mm³ of blood compared to 5M in RBCs and are significantly larger at ~15 µm in diameter compared to ~7.5 µm in RBCs.
• Leukocytes are complete, functioning cells, w/ nuclei & organelles
• For protection, not transport.
• The Differential WBC count includes:
  • The Granulocytes: Neutrophils 40-70%, Eosinophils 1-4%, and Basophils 0-1%.
  • The Agranulocytes: Lymphocytes 20 -45% and Monocytes 4 - 8%.
• There are 5 main types of Leukocytes in total: Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes.
• Granulocytes have lobed nuclei, and granular cytoplasm. They develop in bone marrow.
• Agranulocytes do not have granules, have regular nuclei, and develop in the lymphatic system.
• Functionally, white blood cells are the major form of defence against attack by potentially harmful foreign organisms such as bacteria, viruses, parasites, fungi etc.
• In their protection role, The granulocytes (neutrophils, basophils & eosinophils), as well as the monocytes, protect the body by phagocytosis (the granules contain enzymes that digest microorganisms) and Lymphocytes are involved in the immune response.

Leukocytes Granulocytes

• Most common leukocyte is Neutrophils as they constitute 60-70% of all leukocytes at 10-15 m diameter about twice that of a RBC.
  • Composed of 3-6 sausage-shaped lobes
  • A powerful phagocyte & the body's first line of defence against bacteria and fungi. They perform phagocytosis.
• They adhere to the objects to and grows pseudopodia and degrade the objects by chemical breakdown.
• Most waste is discharged from the cell, although some is retained creating lipofuscin deposits. Eventually the neutrophil itself is destroyed and in turn phagocytosed by monocytes (see later).
• Eosinophils constitute about 1-4% of all WBCS, 9 m diameter in-between neutrophils and RBCs with the distinctive Bilobed nucleus (“earmuffs”).
• Attack foreign objects too large for phagocytosis (e.g., worms & other multicellular parasites) and also involved in allergy & asthma, and have a possible role in blood clotting.
• Basophils stand for about 0.5-2% of all leukocytes (the rarest WBC), 10-15 m diameter similar to neutrophils) featuring a Nucleus which is often S- or U-shaped.
  • They contain the inflammatory chemical Histamine which acts as a vasodilator.
• They act like mast cells (see later lectures) attracting other WBCs to an inflamed site and contain anticoagulant heparin, which prevents blood from clotting too quickly.

Leukocytes Agranulocytes

• Representing about 3-8% of WBCS, Monocytes are Large ~18 m and upon leaving the blood stream and enter tissue they mature into even larger (80 m) macrophages ("big eaters”).
• Featuring a Convoluted bilobed ("kidney shaped") nucleus they Serve multiple roles in immune function.
• In extracellular tissue, monocytes differentiates into macrophages or dendritic cells.
• Macrophages are specialised phagocytes that consume foreign matter and also release cytokines.
• Macrophages can further differentiate into specialized macrophages (e.g., histiocytes in connective tissue)
• Dendritic cells process antigen material and present it on the cell surface to the T cells of the immune system, unrelated to the dendrites of neurons.

Lymphocytes

• Lymphocytes Make up about 25% or more of WBCS and develop from their own stem cell line and come in main of 3 subtypes;
  • T lymphocytes (T cells) act directly against virus-infected cells & tumour cells (after priming by antigen presenting cells).
  • B lymphocytes (B cells) give rise to plasma cells, which produce antibodies that are released to the blood and Natural Killer cells (NK cells) attack virus infected cells.
• The Immune system responds rapidly in the innate immune system, and more specific in other form involving the adaptive immune response.

Lymphocytes & immune response

• The first 4 WBCs, as well as NK cells are part of the generic innate immune response.
• B&T lymphocytes, on the other hand, provide more specific adaptive immunity
• T-lymphocytes develop in the thymus & mediate 'cellular immunity' as they directly kill infected cells
• B-lymphocytes develop in bone marrow, and mediate 'humoral immunity' (antibody mediated immunity) via plasma cells which produce antibodies
  • That then produce antibodies: Y-shaped proteins that "lock on” to a particular antigen & perform various functions, including directly attaching the cell or signalling for phagocytes.
• When exposed to a pathogen, the immune system activates specific T cells and B cells producing specific antibodies.
  • This takes several days, memory cells are produced in case re-infection occurs.
  • Conventional vaccines use altered version to trigger this memory.

Development of Leukocytes

• Erythropoiesis (development of RBCs) stands for an example of haemopoiesis
• The key question remains as to how many Stem Cells are requried to generate RBCs (5 types) and platelets are required.
• Two extremes exist: Monophyletic (one cell gives rise) and Polyphyletic (cells have own stem cells)
• However, true answer is somewhere in between with 2 cell types, one for lymphocytes and one for cells, hence Hameopoiesis is a limited type of phyllectic system.

Thrombocytes

• Thrombocytes (platelets) are about ~2 m in diameter and are anucleate.
  • Are fragments of huge megakaryocytes (160 m in diameter), and they split to form ~4000 platelets
  • A megakaryocyte presses against a sinusoid wall to extend cytoplasmic extensions to then eventually rupture and flow around sealing the cylinder to form disc shape.
• Thrombocytes (platelets) have 250,000 - 400,000 mm³ blood and the span 5-14 day with a key role to to clotting.

Haemostasis

• Haemostasis is the name for blood loss prevention and it has 3 phases: Vascular spasms, platelet plug formation and coagulation.
  • Vascular spasms reduce blood loss for about 20 minutes, buying time.
• For platelets adherence to be possible, nitric oxide and prostacyclin release for aggregation needs to occur.
• This activates Vascular and Platelet actions with stick swelling, and chemicals release.
• Platelet plugs (fibre reinforces) with Fibrin and Plasma processes and by cell chemicals
  • Intrinsic and Extrinsic cell action which occurs via blood cells with a 3-6 seconds on average (18 min max)