THE BLOOD

Prof. Atsma 2005, 2007, 2010

The following is a narrative summary of the topic. Click here for the blood "Classroom Notes" that you can print out and bring to class to save yourself a lot of note-taking.

Blood is a 'connective tissue' which chemically connects all of the interdependent, specialized tissues in the body. People have approximately 1 - 1.5 gallons (4-6 liters) of blood depending on overall body size. Its slightly alkaline average pH of 7.4 is not surprising when one considers the large amount of H+-absorbing molecules like proteins which are present. Its average temperature of about 100oF (38oC) also makes sense when one considers that areas reddened by extra blood flow often seem warm.

The blood is divided into two components - the plasma and the formed elements (mostly red blood cells, but also white blood cells and platelets).

Plasma

Most important nutrients (glucose, ions, amino acids, etc.), wastes, and some gasses are simply dissolved in the plasma. Hormones and other molecules relying upon the blood for transportation are also found either dissolved or suspended in plasma. The most diverse group of molecules found in plasma are the proteins (i.e. albumin, antibodies, clotting). The proteins and electrolytes dissolved in plasma contribute to its osmotic pressure. By making the plasma hypertonic to most body fluids, water is held in the blood vessels which would otherwise slowly leak away.

Plasma contains more protein than most body fluids and with good reason. Clotting proteins, which will be discussed later in greater detail, are necessary for the blood to protect itself from blood loss. Transport proteins, including lipoproteins, carry insoluble materials for the blood. Immunoglobulins (aka antibodies) can agglutinate or otherwise destroy pathogens and other foreign substances.

Formed Elements

Formed elements are so-named because they are formed in the red bone marrow by a process generally referred to as hemopoiesis. The erythrocytes and leukocytes arise from stem cells called hemocytoblasts, and platelets come from megakaryocytes.

Erythrocytes

Also called red blood cells or "RBC's," erythrocytes are incapable of maintaining themselves for more than about 4 months, since they expel their nucleus in order to fill with more hemoglobin and take on a special "biconcave" shape. This shape makes the cells more flexible, allows them to stack when pushed through narrow vessels, and provides more surface area for gas exchange. The hemoglobin found filling RBC’s is a protein which coils around an iron atom such that the iron easily picks up oxygen at the lungs, but lets go of it when reaching oxygen-poor tissues.

RBC production or, erythropoiesis, is stimulated when certain kidney cells detect low blood oxygen levels and release a hormone (erythropoietin). The hormone stimulates hemocytoblasts in the red bone marrow to divide and begin faster RBC production. Thus, only low oxygen levels will cause an increase in our number of RBC's. To summarize, hemocytoblasts divide and become erythroblasts, which turn nearly all of their energy to hemoglobin production. When nearly full of hemoglobin and rough ER needed to make hemoglobin, the cell expels its nucleus and becomes a reticulocyte. The ER deteriorates as the cell finishes filling with hemoglobin and takes on the biconcave shape of a mature erythrocyte. It is normal to have a small percentage of immature reticulocytes circulating in the blood, however a significant proportion suggests a problem where erythropoiesis is being pushed along to quickly, perhaps by internal bleeding or premature destruction of RBC's.

Hemoglobin is mostly a protein composed of four polypeptide chains, each with an iron-containing heme molecule at its center. Hemoglobin's proteins coil around an iron atom such that iron forms a reversible bond with oxygen. The iron easily picks up oxygen at the lungs, but lets go of it when reaching oxygen-poor tissues, making hemoglobin an excellent oxygen-transporting molecule.

When an erythrocyte ages, it becomes brittle due its inability to make materials it needs to properly maintain itself. The human body, being very efficient at recycling, has created the perfect environment in the liver and spleen for old, fragile erythrocytes to break up. Macrophages and other cells in these two organs break down the proteins into amino acid for re-use by body cells. The iron and heme molecules present bigger challenges. The iron is picked up by a molecule called transferrin and carried to erythroblasts that need it. Excess iron can be stored by other molecules in the liver and bone marrow called ferritin and hemosiderin. The heme molecule is a bit more dangerous as it is loaded with potentially toxic nitrogenous portions. It is converted to biliverdin and bilirubin, which the liver can recycle into the mixed chemical soup commonly known as bile. Although bile is a substance useful to the digestive system, it is also partly an excreted waste material. Metabolites of bilirubin are excreted in the feces and urine. When bilirubin cannot be excreted as part of bile, it can accumulate in body fluids and cause jaundice.

HEMATOCRIT: Since erythrocytes make up most of the formed elements, measuring the percentage of cells vs. plasma provides an estimate the percentage of RBC's in whole blood. Hematocrit measurements of 40-52% are considered normal for males, and 37-47% for females. (Note: this percentage varies slightly among experts and authors.) The affect of the male's average extra muscle mass on oxygen levels accounts for much of the sexual difference in hematocrit. The term anemia relates to a wide variety of disorders in which the blood has a reduced oxygen-carrying capacity. Low iron, poor absorption of protein, chronic blood loss, and improper blood cell formation are the main causes of the various anemias. Polycythemia is the term used to describe abnormally high RBC counts, and can be due to many different lung diseases, or can be the natural result of living in high-altitude environments.

Blood Typing: Certain genes control the "shape" of the marker molecules that stick out of the cell membrane. The immune system learns to recognize the "faces" of all body cells and knows a stranger when it sees one. Some leukocytes make antibodies, which are proteins that can lock onto these foreign shapes like chemical handcuffs and clump them together for removal by other WBC's. This clumping of antigens when antibodies attach is called agglutination.

Molecule shapes on the surface of human red blood cells come in a few easily recognizable varieties (A & B). Your blood type simply relates to whether you have molecule shape A, B, both ("type AB"), or neither ("type O"). The "Rh" marker molecules are simply either present or absent, and are thus designated by a "+" (present) or "-" (absent).  Since your immune system only "knows" to ignore the shapes it has seen in your body, it will produce antibodies against these other "foreign" varieties of RBC's if they enter your body.  

Erythrocytes and Blood Typing

Antibodies added to each drop:  

Anti-A   Anti-B

Anti-A   Anti-B

Anti-A   Anti-B

Anti-A   Anti-B

Agglutination Response

+       -

-       +

+       +

-       -

Blood type

A

B

AB

O

Antibodies present in vivo

B

A

Neither

A & B

Note: "+" = clumping or agglutination; "-" = no clumping or agglutination.

Leukocytes

Also called white blood cells or WBC’s, leukocytes are divided into granular (neutrophils, eosinophils, basophils) and agranular (lymphocytes and monocytes) categories. The characteristics and functions of all of these leukocytes are summarized nicely in your lab manual and textbook. A differential white blood cell count tells us which WBC's (if any) are present at unusually high levels. Since each leukocyte seems to have a specialty, elevated levels of a particular WBC may be an indicator of the type of disease the body is trying to counter.

Percentages in the following table are approximates for a healthy individual.

Leukocytes

Neutrophils

most numerous of all circulating leukocytes (65%); elevated in acute infections; have very faint pinkish granules and a multi lobed nucleus.

Eosinophils

relatively rare (1-5%); elevated in parasitic infections and allergic responses; have fairly dark granules that range in color from light red to dark red (the darkest may have a slight purple tint, but not as purple as the nucleus); bilobed nucleus.

Basophils

very rare granular leukocyte (<1%) associated with allergic and inflammatory responses; have a bilobed nucleus and purple granules the same color as the nucleus (therefore the nucleus may be hidden by the similarly colored granules).

Lymphocytes

most numerous of the agranular leukocytes (25%); associated with the specific immune system (may either produce antibodies or directly attack foreign substances); large purple nucleus with a small, clear, crescent moon-shaped area of cytoplasm.

Monocytes

large leukocyte with a somewhat regular but distorted nucleus (i.e. kidney bean shaped); (8%) elevated in chronic infections.

Platelets

These small fragments of large stem cells in the bone marrow called megakaryocytes are specialists in assisting with the clotting process. They become sticky when near damaged tissues (broken blood vessel walls) and can block small openings the same way that damp, sticky salt clogs up the small holes of a salt shaker. They also release chemicals from their cytoplasm which further stimulate the clotting process (see "clotting" below).

CLOTTING

Clotting involves both platelets and plasma proteins. Prothrombin and fibrinogen are soluble proteins made by the liver. Damaged cells and tissues release chemicals that eventually cause the local production of a prothrombin activator (PTA), which converts prothrombin to thrombin. Thrombin then helps to convert fibrinogen to fibrin, an insoluble protein that coagulates blood. Together, the fibrin net and platelet plug block the flow of blood from a damaged vessel.

The Process:
It is best to study clotting within the larger context of blood homeostasis. The response to damaging a blood vessel begins with the vascular spasm, or immediate constriction of the damaged blood vessel in order to help reduce blood loss until clotting can take place. Next, platelet plug formation occurs, which is not just a simple "corking" of the opening, but rather a complex biochemical entity which facilitates the next stage.

Then, depending upon the source of PTA, coagulation follows. The extrinsic pathway (tissues release the PTA) or intrinsic pathway (platelets release the PTA) both lead to fibrin production as previously discussed. This is often described as a rare example of a place where the body uses positive feedback, as more PTA produces more fibrin, which traps more platelets, which causes the release of more PTA, and so on….

Once a secure clot is formed, clot retraction follows. Now that the bleeding as been mostly stopped, those multitalented platelets contract (yes, they actually contain some actin and myosin), and the response may switch to fighting infection and repairing the damaged area. An enzyme called plasmin, which is activated by chemicals found around a damaged vessel, begins digesting fibrin. This slow process of fibrinolysis eventually digests the clot.

Things affecting blood clotting:
Because the liver needs vitamin K in order to synthesize prothrombin and other clotting factors, it is critical to proper clotting homeostasis. We normally have enough vitamin K because it is made by bacteria in the large intestine in quantities large enough to supplement the relatively small amount found in the average person's diet. Agents causing liver damage and antibiotics which kill the helpful vitamin K-producing bacteria impair coagulation. Diseases such as hemophilia which interfere with the ability to make one or more clotting factor also impair coagulation.

Some anticoagulants such as coumadin work mainly by impairing vitamin K. Others such as heparin seem to promote the inactivation of one or more clotting factors. Prostaglandin inhibitors such as aspirin disable the ability of platelets to assist with the clotting pathways. Finally, plasmin activators such as streptokinase directly accelerate fibrinolysis.

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