Human Physiology - Blood & Body Defenses

BIO 301
Human Physiology

& Body Defenses I

Functions of Blood:

oxygen & carbon dioxide
nutrients
waste products (metabolic wastes, excessive water, & ions)

3 - Protection - clotting mechanism protects against blood loss & leucocytes provide immunity against many disease-causing agents

Components of Blood - average adult has about 5 liters (about 5 qts):

1 - Formed elements:

Red blood cells (or erythrocytes)
White blood cells (or leucocytes)
Platelets (or thrombocytes)

2 - Plasma = water + dissolved solutes

Red blood cell, platelet, and white blood cell

Red Blood Cells (or erythrocytes):

2 - lack a nucleus & cannot reproduce (average lifespan = about 120 days)

3 - transport hemoglobin (each RBC has about 280 million hemoglobin molecules)

4 - Typical concentration is 4-6 million per cubic mm (or hematocrit [packed cell volume] of about 42% for females & 45% for males)

5 - contain carbonic anhydrase (critical for transport of carbon dioxide)

Determining the hematocrit

Erythropoiesis = formation of erythrocytes

the body must produce about 2.5 million new RBCs every second
in adults, erythropoiesis occurs mainly in the marrow of the sternum, ribs, vertebral processes, and skull bones
begins with a cell called a hemocytoblast or stem cell (below)
rate is regulated by oxygen levels:

hypoxia (lower than normal oxygen levels) is detected by cells in the kidneys
kidney cells release the hormone erythropoietin into the blood
erythropoietin stimulates erythropoiesis by the bone marrow

training.seer.cancer.gov

Three main classifications of blood cells derive from haematopoietic stem cells (HSCs) (Katsura 2002).

Myeloid cells. This includes macrophages (monocytes) and granular white blood cells (or granulocytes; neutrophils, basophils and eosinophils). Macrophages have a role in adaptive immunity, cooperating with T and B cells through antigen presentation and the production of cytokines.

Erythroid-megakaryocytes. Erythrocytes (red blood cells) carry oxygen through blood vessels, whereas platelets derived from megakaryocytes work to prevent blood loss.

Lymphoid cells. This includes T-cells and B-cells. Natural killer (NK) cells are thought to be the prototype of T cells. Thymic, as well as pre-thymic, T-cell progenitors are able to generate dendritic cells. B cells secrete antibodies.

Hemoglobin

composed of globin (made up of 4 highly folded polypeptide chains) + 4 heme groups (with iron)
each molecule can carry 4 molecules of oxygen
called oxyhemoglobin when carrying oxygen & called reduced hemoglobin when not carrying oxygen
can also combine with carbon dioxide & helps transport carbon dioxide from the tissues to the lungs

The binding and release of oxygen illustrates the structural differences between oxyhemoglobin and reduced (or deoxy-) hemoglobin. Only one of the four heme groups is shown
(Source: wikipedia).

White blood cells (or leucocytes or leukocytes):

have nuclei & do not contain hemoglobin
typical concentration is 5,000 - 9,000 per cubic millimeter
types of WBCs:

granular white blood cells include:

neutrophils (50 - 70% of WBCs)
eosinophils (1 - 4%)
basophils (less than 1%)

agranular (or non-granular) white blood cells include:

lymphocytes (25 - 40%)
monocytes (2 - 8%)

Granular white blood cells contains numerous granules in the cytoplasm, & their nuclei are lobed. Agranular white blood cells have few or no granules in the cytoplasm & have a large spherical nucleus. Granular white blood cells are produced in the bone marrow, while agranular white blood cells are produced in lymph tissue, e.g., Lymph nodes (specialized dilations of lymphatic tissue which are supported within by a meshwork of connective tissue called reticulin fibers and are populated by dense aggregates of lymphocytes and macrophages).

The primary functions of the various white blood cells are:

Neutrophils - phagocytosis (bacteria & cellular debris); very important in inflammation
Eosinophils - help initiate and sustain inflammation and can activate T-cells (directly by serving as antigen-presenting cells and indirectly by secreting a variety of cytokines. Eosinophils can also kill bacteria by quickly releasing mitochondrial DNA and proteins (described below).

Eosinophils respond to diverse stimuli, including tissue injury, infections, allografts, allergens, and tumors. Eosinophils can also release a variety of cytokines, chemokines, lipid mediators, and neuromodulators. Eosinophils directly communicate with T cells and mast cells. Eosinophils activate T cells by serving as antigen-presenting cells.

Basophils - along with mast cells, play a role in inflammation and allergic responses

Release of histamine (that contributes to the 'symptoms' of allergies) by mast cells requires the production of antibodies (IgE) by B-cells and
that process is regulated, in part, by cytokines produced by basophils (Bischoff 2007).

Monocytes - phagocytosis (typically as macrophages in tissues of the liver, spleen, lungs, & lymph nodes) & also important antigen-presenting cells

Once distributed through the blood stream, monocytes enter other tissues of the body such as the liver (Kupffer cells), lungs (alveolar macrophages), skin (Langerhans cells), and central nervous system (microglia) (Gordon 2003).

Lymphocytes - immune response (including production of antibodies)

Eosinophils (in green with red nucleus) catapult their mitochondrial DNA out of the cell, forming tangled traps (red) that ensnare foreign bacteria.
(Photo credit: Hans-Uwe Simon, Institute of Pharmacology, University of Bern, Switzerland)

Catapult-like release of mitochondrial DNA by eosinophils -- Although eosinophils are considered useful in defense mechanisms against parasites, their exact function in innate immunity remains unclear. Yousefi et al. (2008) found that eosinophils in the gastrointestinal tract release mitochondrial DNA in a rapid, catapult-like manner—in less than one second. The mitochondrial DNA and proteins released by the eosinophils bind to and kill bacteria. This is a previously undescribed mechanism of eosinophil-mediated innate immune responses that might be crucial for maintaining the intestinal barrier function after inflammation-associated epithelial cell damage, preventing the host from uncontrolled invasion of bacteria.

Some important characteristics of White Blood Cells (particularly neutrophils):

diapedesis

3 - capable of ameboid movement

4 - exhibit chemotaxis (attracted to certain chemicals, such as those released by damaged cells)

Phagocytosis

Lymph system

Chemotaxis & ameboid movement

Neutrophil moving to site of infection

Platelets (or thrombocytes)

1 - formed in the bone marrow from cells called megakaryocytes

Megakaryocytes. (A) & (B) immature cells. (C) mature cell producing platelets.
(Source: Battinelli et al. 2001).

2 - have no nucleus, but can secrete a variety of substances & can also contract (because they contain actin & myosin)

3 - normal concentration in the blood is about 250,000 per cubic millimeter

4 - remain functional for about 7 - 10 days (after which they are removed from the blood by macrophages in the spleen & liver)

5- play an important role in hemostasis (preventing blood loss)

Plasma:

1 - Water - serves as transport medium; carries heat

2 - Proteins

Albumins

60-80% of plasma proteins
most important in maintenance of osmotic balance
produced by liver

Globulins

alpha & beta

some are important for transport of materials through the blood (e.g., thyroid hormone & iron)
some are clotting factors
produced by liver

gamma globulins are immunoglobulins (antibodies) produced by lymphocytes

Fibrinogen

important in clotting
produced by liver

Twenty-two proteins constitute $~$ 99% of the protein content of plasma (Tirumalai et al. 2003).

3 - Inorganic constituents (1% of plasma) - e.g., sodium, chloride, potassium, & calcium

4 - Nutrients - glucose, amino acids, lipids & vitamins

5 - Waste products - e.g., nitrogenous wastes like urea

6 - Dissolved gases - oxygen & carbon dioxide

7 - Hormones

Hemostasis - prevention of blood loss from broken vessel (check this Hemostasis animation):

1 - Vascular spasm - vasoconstriction of injured vessel due to contraction of smooth muscle in the wall of the vessel. This 'spasm' may reduce blood flow & blood loss but will not stop blood loss.

2 - Formation of a platelet plug - platelets aggregate at the point where a vessel ruptures. This occurs because platelets are exposed to collagen (a protein found in the connective tissure located just outside the blood vessel). Upon exposure to collagen, platelets release ADP (adenosine diphosphate) & thromboxane. These substances cause the surfaces of nearby platelets to become sticky and, as 'sticky' platelets accumulate, a 'plug' forms.

3 - Blood coagulation (clotting):

Used with permission of Michael W. King, Ph.D / IU School of Medicine

The result of all of this is a clot - formed primarily of fibrin threads (or polymers), but also including blood cells & platelets.

Blood clots in the right places prevent the loss of blood from ruptured vessels, but in the wrong place can cause problems such as a stroke (see below under inappropriate clotting).

Clot retraction:

"tightening" of clot
contraction of platelets trapped within clot shrinks fibrin meshwork, pulling edges of damaged vessel closer together

Over time (with the amount of time depending on the amount of damage), the clot is dissolved and replaced with normal tissue.

Fibrinolysis:

dissolution of clot
mechanism = plasminogen (a plasma protein) is activated by many factors & becomes PLASMIN. Plasmin then breaks down fibrin meshwork & phagocytic WBCs remove products of clot dissolution

Blue arrows = stimulation; red arrows = inhibition. tPA is released by damaged endothelium
(Source: en.wikipedia.org/wiki/Fibrinolysis)

Inappropriate clotting:

thrombus - clot formed in an intact vessel, possibly due to:

roughened vessel walls (atherosclerosis; see normal & occluded coronary arteries below)
slow-moving blood (e.g., in varicose veins) = small quantities of fibrin form & accumulate
check this animation about deep vein thrombosis

embolus - 'moving' clot

Source: http://www.ors.od.nih.gov/medart/portfolio/Donny/embolus.html

Thrombus and embolus

Excessive bleeding:

Hemophilia

genetic 'defect'
inability to produce certain clotting factor(s)

Thrombocytopenia

abnormally low platelet count
most persons have idiopathic thrombocytopenia (= unknown cause) while in others it's an autoimmune disease

Thrombocytopenia is a condition where platelet counts are lower than normal, potentially leading to mild to serious bleeding. This bleeding can happen inside the body (internal bleeding) or on the skin. A normal platelet count is 150,000 to 450,000 platelets per microliter of blood. A count of less than 150,000 platelets per microliter is lower than normal, but the risk for serious bleeding doesn't occur until the count becomes very low—less than 10,000 or 20,000 platelets per microliter. Milder bleeding sometimes occurs when the count is less than 50,000 platelets per microliter. Several factors can cause a low platelet count, such as:

The bone marrow doesn't make enough platelets.
The bone marrow makes enough platelets, but the body destroys them (autoimmunity) or uses them up.
The spleen holds onto too many platelets. The spleen is an organ that normally stores about one-third of the body's platelets. It also helps your body fight infection and remove unwanted cell material.
A combination of the above factors.

How long thrombocytopenia lasts depends on its cause. It can range from days to years. The treatment for this condition also depends on its cause and severity. Mild thrombocytopenia most often doesn't need treatment. If the condition is causing serious bleeding, or if you're at risk for serious bleeding, you may need medicines or blood or platelet transfusions. Rarely, the spleen may need to be removed. Thrombocytopenia can be fatal, especially if the bleeding is severe or occurs in the brain. However, the overall outlook is good, especially if the cause of the low platelet count is found and treated (Source: NHLBI).