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An overview of the cardiovascular system

.

 Driven by the pumping of the heart, blood flows through the pulmonary and systemic circuits in sequence.  Each circuit begins and ends at the heart and contains arteries, capillaries, and veins 2 maria immaculata iwo, sf itb

Heart Vessel Blood

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Cardiovascular System

Main component

Heart

   Blood : fluid circulated Heart : pump (pulmonary & systemic circuits) Vessel: Artery & vein Blood

Bood vessel

(

artery, arteriole

)

Capillary exchange tissue Lung Systemic circuit Pulmonary circuit Blood vessel (Vein) Heart Excretion (Kidney) Aorta (Artery) Lymphatic vessel (Lymphatic system)

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   Serum protein & lipids Blood group & Rh factor Blood transfusion • Functions of the blood • Formation of Blood Cells • Blood component: • Blood elements : • Red Blood Cells – Oxygen Transport – – – Carbon Dioxide Transport Anemia Blood Groups • White Blood Cells – Lymphocytes – – – – Monocytes Neutrophils Eosinophils Basophils • Platelets • Plasma 5

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• • If one takes a sample of blood, treats it with an agent to prevent clotting, and spins it in a centrifuge, – the red cells settle to the bottom – the white cells settle on top of them forming the " buffy coat ".

– The fraction occupied by the red cells is called the hematocrit.

Normally it is approximately

45%.

– Values much lower than this are a sign of anemia .

Blood fluid:

- Serum?

- Plasma?

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Plasma (46-63%)

Formed elements (37-54% 8

Formed elements

Function & description

Source Plasma Function Source

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10

11

12

Blood Plasma

  

Plasma protein 7% Other solutes 1% Water 92% Blood

A sample of blood is approximately 55% plasma and 45% formed elements.

Plasma Formed (55%) elements (45%)

Plasma is approximately 92% water and contains – proteins to regulate the osmotic pressure of blood, – protein for the clotting process and – antibody proteins that work with the immune system to protect your body from invading pathogens.

– Electrolytes, hormones, nutrient and some blood gases are transported in the blood plasma. 13

Plasma Constituent

Water

Major functions

Solvent for carrying other substances (organic and inorganic molecules, formed elements, and heat)

Salts (eletrolytes):

Sodium, Potassium Calcium, Magnesium Chloride, Bicarbonate Plasma proteins -

Albumin

Osmotic balance, pH buffering, and regulation of membrane permeability -

Fibrinogen

-

Globulins

Regulatory proteins <1%) Major contribution to osmotic pressure of plasma, transport lipids, steroid, hormone

Essential component of blood clotting system, can be converted to insoluble fibrin

Defense (antibodies), transport ions, hormone, and lipid Enzymes, proenzymes, hormones 14

Plasma Constituent Other solutes -

Electrolytes

Major functions

Normal extracellular fluids ion composition essential for vital cellular activities. Ions contribute to osmotic pressure of body fluids. Major plasma electrolytes are Na + , K + , Ca 2+ , Mg 2+ , Cl , bicarbonate, phosphate, sulfate ¯ ¯ - Organic nutrients Used for ATP production, growth, and maintenance of cells; include lipids (fatty acids, cholesterol, glycerides), carbohydrates (primarily glucose), and amino acids - Organic wastes Carried to sites of breakdown or excretion, include urea, uric acid, creatinine, billirubin, ammonium ions

•

The Formed Elements

The formed elements may be organized into three group of cells: - the red blood cells or erythrocytes, - the white blood cells or

leukocytes

, and - the

platelets.

• When stained, each group is easy to identify with a microscope : The red cells are erythrocytes, - the stained cells are leukocytes , and - the small cell fragments between the red and white cells are platelets.

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Blood elements

There are seven types of cells and cell fragments : 

red blood cells

(RBCs) or erythrocytes 

platelets

or

thrombocytes

 five kinds of white blood cells (WBCs) or

leukocytes

- Three kinds of

granulocytes : neutrophils eosinophils basophils

Two kinds of leukocytes without granules in their cytoplasm (

agranulocytes ) lymphocytes monocytes

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Blood characteristic

 Blood is a composite of fluid connective tissue that flows through the vessels of the vascular system.  In response to injury, blood has the intrinsic ability to change from a liquid to a gel so as to clot and stop bleeding.  Blood comprises cells and cell pieces that are collectively called the formed elements . These cells are carried in an extracellular fluid called blood plasma .

Blood characteristic

•

Blood inside the vein and artery

±

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

C (Higher than body temperature



Viscosity: 5 x ŋ water

• •

pH: 7.35-7.45 (

±

7.4) Total Volume:

± •

7% body weight Man : 5 - 6 L

•

Women: 4 - 5 L

Functions of the blood

• Blood performs two major functions: 

transport

through the body of – oxygen and carbon dioxide – food molecules (glucose, lipids, amino acids) – ions (e.g., Na + , Ca 2+ , HCO3 − ) – wastes (e.g., urea) – – hormones heat

defense

of the body against infections and other foreign materials. All the

WBCs

participate in these defenses.

Blood Function

 Blood has many diverse functions, all relating internal environment.

to supplying cells with essential materials and maintaining the  Red blood cells transport respiratory gases to trillions of cells in the body.  The blood controls the chemical composition of all interstitial fluid by regulating pH and electrolyte levels.  White blood cells are part of the immune system and protect our body from microbes by producing antibody molecules and phagocytizing foreign cells.

THE FORMATION OF BLOOD CELLS ( HEMATOPOIESIS )

• • • All the various types of blood cells are produced in the bone marrow (some 10 11 of them each day in an adult human!). arise from a single type of cell called a

hematopoietic stem cell

— an "adult" multipotent stem cell .

These stem cells – are very rare (only about one in 10,000 bone marrow cells); – are attached (probably by adherens junctions ) to osteoblasts lining the inner surface of bone cavities; – express a cell-surface protein designated CD34; – produce, by mitosis,

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Which path is taken is regulated by the need for more of that type of blood cell which is, in turn, controlled by appropriate

cytokines and/or hormones .

• • •

Examples:

Interleukin-7 (IL-7) is the major cytokine in stimulating bone marrow stem cells to start down the path leading to the various

lymphocytes

(mostly B cells and T cells ).

Erythropoietin

(

EPO

), produced by the kidneys, enhances the production of red blood cells (RBCs).

Thrombopoietin

(TPO), assisted by Interleukin-11 (IL-11), stimulates the production of megakaryocytes. Their fragmentation produces

platelets

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• Granulocyte-macrophage colony-stimulating factor (GM-CSF), its name suggests, sends cells down the path leading to both those cell types. In due course, one path or the other is taken.

as – Under the influence of granulocyte colony-stimulating factor (G-CSF), they differentiate into

neutrophils

. – Further stimulated by interleukin-5 (IL-5) they develop into

eosinophils

. – Interleukin-3 (IL-3) participates in the differentiation of most of the white blood cells but plays a particularly prominent role in the formation of

basophils

(responsible for some allergies ). – Stimulated by macrophage colony-stimulating factor (M-CSF) the granulocyte/macrophage progenitor cells differentiate into

monocytes, macrophages

, and dendritic cells (DCs).

Myeloid stem cells Pro genitor cells blast cells Hemocytoblasts Lymphoid stem cells

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Red Blood Cells (erythrocytes)

The most numerous type in the blood.  Women average about 4.8 million of these cells per cubic millimeter ( mm3; which is the same as a microliter [µl] ) of blood.  Men average about 5.4 x

10 6

per µl.  These values can vary over quite a range depending on such factors as health and altitude .  Peruvians living at 18,000 feet may have as many as 8.3 x 10 6 RBCs per µl.)

Red Blood Cells (erythrocytes)

• • Red blood cells (abbreviated RBCs, also called erythrocytes from erythro = red + cyte = cell) are continually produced in bone marrow and - recycled in spleen . • In mature form they lack nuclei and most cytoplasmic structures; they are little more than discoid, flexible bags of hemoglobin

.

Red Blood Cells (erythrocytes)

• • • • RBC precursors mature in the bone marrow closely attached to a macrophage. They manufacture

hemoglobin

until it accounts for some 90% of the dry weight of the cell. The

nucleus is squeezed out of the cell

ingested by the macrophage. and is This scanning electron micrograph (courtesy of Dr. Marion J. Barnhart) shows the characteristic

biconcave shape

of red blood cells 

Red Blood Cells (erythrocytes)

• • • • • Thus RBCs are terminally differentiated; that is, they can never divide . They live about 120 days and then are ingested by phagocytic cells in the liver and spleen. Most of the iron in their hemoglobin is reclaimed for reuse. The remainder of the heme portion of the molecule is degraded into bile pigments and excreted by the liver. Some 3 million RBCs die and are scavenged by the liver each second. Red blood cells are responsible for the transport of

oxygen

and carbon dioxide.

Oxygen Transport

• • • • • In adult humans the hemoglobin (Hb) molecule consists of four polypeptides: – two alpha (α) chains of 141 amino acids and – two beta (β) chains of 146 amino acids Each of these is attached the prosthetic group heme. There is one atom of iron at the center of each heme. One molecule of oxygen can bind to each heme.

• • • The reaction is reversible. Under the conditions of lower temperature , higher pH , and increased oxygen pressure in the capillaries of the lungs , the reaction proceeds to the right. The purple-red deoxygenated hemoglobin of the venous blood becomes the bright-red oxyhemoglobin of the arterial blood . Under the conditions of higher temperature, lower pH, and lower oxygen pressure in the tissues, the reverse reaction is promoted and oxyhemoglobin gives up its oxygen.

Carbon Dioxide Transport

•  Carbon dioxide (CO 2 ) combines with water forming carbonic acid, which dissociates into a hydrogen ion (H + ) and a bicarbonate ions : CO 2 + H 2 O ↔ H 2 CO 3 ↔ H + + HCO 3 − 95% of the CO 2 blood cells: – generated in the tissues is carried in the red It probably enters (and leaves) the cell by diffusing through transmembrane channels in the plasma membrane. (One of the proteins that forms the channel is the D antigen that is the most important factor in the Rh system of blood groups.)

Carbon Dioxide Transport

 Only about 5% of the CO 2 generated in the tissues dissolves directly in the plasma. (A good thing, too: if all the CO 2 we make were carried this way, the pH of the blood would drop from its normal 7.4 to an instantly-fatal 4.5!) • When the red cells reach the lungs, these reactions are reversed and CO 2 is released to the air of the alveoli.

Carbon Dioxide Transport

•  Once inside, about one-half of the CO bound to hemoglobin (at a site different from the one that binds oxygen). 2 is directly The rest is converted — following the equation above — by the enzyme carbonic anhydrase into – bicarbonate ions that diffuse back out into the plasma and – hydrogen ions (H + ) that bind to the protein portion of the hemoglobin (thus having no effect on pH).

Recycling of red blood cell components

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• •

Anemia

Anemia is a shortage of RBCs and/or the amount of hemoglobin in them.

Anemia has many causes. One of the most common is an inadequate intake of iron in the diet. •

Blood Groups

Red blood cells have surface antigens that differ between people and that create the so-called blood groups such as the ABO system and the Rh system.

The ABO Blood Groups

• • • • The ABO blood groups were the first to be discovered (in 1900) and are the most important in assuring safe blood transfusions. The table shows the four ABO phenotypes ("blood groups") present in the human population and the genotypes that give rise to them. When red blood cells carrying one or both antigens exposed to the corresponding antibodies , they agglutinate; that is, clump together. are People usually have antibodies against those red cell antigens that they lack. 40

Blood Group A B AB

The ABO Blood Groups

Antigens on RBCs A Antibodies in Serum Genotypes

Anti-B

AA

or

AO

A B

and

B

Anti-A Neither

BB

or

AB BO

O

Neither Anti-A and Anti-B

OO

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•

Other blood groups

Several other blood group antigens have been identified in humans.

– Some examples: MN, Duffy, Lewis, Kell. •

They, too, may sometimes cause

– transfusion reactions and even – hemolytic disease of the newborn • in cases where there is no ABO or Rh incompatibility. 42

• Human red blood cells before (left) and after (right) adding serum containing anti-A antibodies. The agglutination reaction reveals the presence of the A antigen on the surface of the cells.

The Rh System

• • • • • • • Rh antigens are transmembrane proteins with loops exposed at the surface of red blood cells. They appear to be used for the transport of carbon dioxide and/or ammonia across the plasma membrane. They are named for the rhesus monkey in which they were first discovered. There are a number of Rh antigens.

Red cells that are "Rh positive" express the one designated D . About 15% of the population have no RhD antigens and thus are "Rh negative". The major importance of the Rh system for human health is to avoid the danger of RhD incompatibility between mother and fetus.

The Rh System

• • • • • • During birth, there is often a leakage of the baby's red blood cells into the mother's circulation. If the baby is Rh positive (having inherited the trait from its father) and the mother Rh-negative, these red cells will cause her to develop antibodies against the RhD antigen. The antibodies, usually of the IgG class red cells of a subsequent Rh+ fetus. , do not cause any problems for that child, but can cross the placenta and attack the This destroys the red cells producing anemia and jaundice. The disease, called erythroblastosis fetalis or hemolytic disease of the newborn, may be so severe as to kill the fetus or even the newborn infant. It is an example of an antibody-mediated cytotoxicity disorder.

White Blood Cells (leukocytes)

• • • • White blood cells are much less numerous than red (the ratio between the two is around 1:700), have nuclei , participate in protecting the body from infection, consist of lymphocytes and monocytes with relatively clear cytoplasm, and three types of granulocytes, whose cytoplasm is filled with granules.

White Blood Cells (leukocytes)

• White blood cells (abbreviated WBCs, also called leukocytes from

leuko = white + cyte = cell

) comprise several distinct cell types,

neutrophils , eosinophils , basophils , lymphocytes

and

monocytes

. – Certain developmental and morphological similarities permit the first three these cells to be usefully grouped together as

granulocytes or polymorphonuclear leukocytes .

– The latter two types are then categorized as

mononuclear leukocytes

.

• •

Lymphocytes

There are several kinds of lymphocytes (although they all look alike under the microscope), each with different functions to perform . The most common types of lymphocytes are –

B lymphocytes

antibodies. ("B cells"). These are responsible for making – T lymphocytes ("T cells"). There are several subsets of these: •

inflammatory T cells

that recruit macrophages and neutrophils to the site of infection or other tissue damage •

cytotoxic T lymphocytes

perhaps, tumor cells (CTLs) that kill virus-infected and, •

helper T cells

by B cells that enhance the production of antibodies

Lymphocytes

• Although bone marrow is the ultimate source of lymphocytes, the lymphocytes that will become T cells migrate from the bone marrow to the thymus where they mature under the influence of thymic hormones • Both B cells and T cells also take up residence in lymph nodes, the spleen and other tissues where they – encounter antigens; – continue to divide by mitosis; – mature into fully functional cells.

Lymphocytes

 Lymphocytes are small cells, 7-9 μm in diameter in blood smears, and are the second most common white blood cell type, comprising about 30 % of the circulating leukoytes.  Lymphocytes have a round heterochromatic (deeply staining) nucleus surrounded by a relatively thin rim cytoplasm. of

Monocytes

• Monocytes leave the blood and become macrophages and

dendritic cells

.  Macrophages are large, phagocytic cells that engulf foreign material (antigens) that enter the body dead and dying cells of the body.

Mononuclear leukocytes comprise both lymphocytes and monocytes . Both cell types work together in immune responses. This scanning electron micrograph (courtesy of Drs. Jan M. Orenstein and Emma Shelton) shows a single macrophage surrounded by several lymphocytes .

• • • • • •

Monocytes

Monocytes are the largest of the leukocytes, and constitute about 5 % of the WBC population in peripheral blood. In blood smears, their nuclei are typically indented, sometimes deeply so, with a kidney-bean or bent-horseshoe shape. Monocytes belong to the same functional population as tissue macrophages. Monocytes/macrophages engulf and digest foreign microorganisms, dead or worn-out cells, and other tissue debris. They interact closely with lymphocytes to recognize and destroy foreign substances. Most ordinary connective tissues contain resident macrophages which normally remain at rest in the tissue. But the normal number of fixed macrophages is supplemented during inflammation by the influx of many monocytes from the blood.

Neutrophils

• • • The most abundant of the WBCs. Neutrophils squeeze through the capillary walls and into infected tissue where they kill the invaders (e.g., bacteria) and then engulf the remnants by phagocytosis . This is a never-ending task, even in healthy people: Our throat, nasal passages, and colon harbor vast numbers of bacteria. Most of these are commensals , and do us no harm. But that is because neutrophils keep them in check. This photomicrograph shows a single neutrophil surrounded by red blood cells

Neutrophils

However,

– heavy doses of radiation – chemotherapy – and many other forms of stress can reduce the numbers of neutrophils so that formerly harmless bacteria begin to proliferate. The resulting opportunistic infection can be life threatening.

Neutrophils

• • • Neutrophils (also called neutrophilic granulocytes, or polymorphonuclear neutrophilic leukocytes, PMNs, or polys) are the most numerous of the leukocytes, about 60% of the white blood cell count. They are about 12 μm in diameter in blood smear preparations (about twice the size of red blood cells). Too many neutrophils is called

neutrophilia

;

Neutrophils

• Neutrophils take their name from the staining properties of their cytoplasmic lysosomal granules (vesicles containing stored lysosomal enzymes). These granules are neutrophilic are stained mildly by both. , meaning they show no special affinity for either acidic or basic stains but – This is in contrast to the specific granules of basophils , which stain with basic stains . eosinophils , which stain red with acidic stains such as eosin, and those of  The nuclei of mature neutrophils are elongated and pinched into several distinct lobes, hence the term

polymorphonuclear.

 Immature neutrophils have a band-shaped nucleus and are hence sometimes called "bands".  Mature neutrophils, in contrast, are called "segs", in reference

to the segmented nucleus.

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• • • • • • •

Eosinophils

Eosinophils (eosinophilic granulocytes) normally comprise less than two to four percent of the peripheral leukocytes. Their specific granules are intense eosinophilic (stained by eosin), hence the name. Eosinophils are about the same size as neutrophils. Their nuclei are typically band shaped (elongated) or two-lobed. The number of eosinophils in the blood is normally quite low (0– 450/µl). However, their numbers increase sharply in certain diseases, especially infections by parasitic worms. Eosinophils are cytotoxic, releasing the contents of their granules on the invader.

Eosinophils

Basophils

• • • • • Basophils (basophilic granulocytes) normally comprise less than 1 % of the peripheral leukocytes. Their specific granules are intense basophilic, hence the name. Like eosinophils, basophils are similar in size to neutrophils . Their nuclei may be band shaped or segmented. Basophils seem to be functionally similar to tissue mast cells, involved in triggering inflammation .

Basophils

• • The number of basophils also increases during infection.

Basophils leave the blood and accumulate at the site of infection or other inflammation. There they discharge the contents of their granules, releasing a variety of mediators such as: – histamine – serotonin – prostaglandins and leukotrienes which increase the blood flow to the area and in other ways add to the inflammatory process. The mediators released by basophils also play an important part in some allergic responses such as – hay fever and – an anaphylactic response to insect stings .

Platelets

• • • Platelets are cell fragments produced from megakaryocytes. Blood normally contains 150,000–450,000 per microliter (µl) or cubic millimeter (mm feedback) mechanism.

3 ). This number is normally maintained by a homeostatic (negative If this value should drop much below 50,000/µl, there is a danger of uncontrolled bleeding because of the essential role that platelets have in blood clotting. Some causes: – certain drugs and herbal remedies; – autoimmunity.

Platelets

• • When blood vessels are cut or damaged, the loss of blood from the system must be stopped before solidification of the blood, a process called coagulation or clotting.

shock and possible death occur. This is accomplished by A blood clot consists of – a plug of platelets enmeshed in a – Network of insoluble fibrin molecules.  Please learn by yourself Details of the clotting process!

Plasma

• • Plasma is the straw-colored liquid in which the blood cells are suspended. Composition of blood plasma

Component

Water ~92

Percent

Proteins Salts Lipids Glucose (blood sugar) 0.6

6–8 0.8

0.1

Plasma

• Plasma transports materials needed by cells and materials that must be removed from cells: – various ions (Na + , Ca 2 +, HCO3 − , etc. – glucose and traces of other sugars – amino acids – other organic acids – cholesterol and other lipids – hormones – urea and other wastes Most of these materials are in transit from a place where they are added to the blood (a "source") – exchange organs like the intestine – to places ("sinks") where they will be removed from the blood. – depots of materials like the liver every cell – exchange organs like the kidney, and skin.

Serum Proteins

• • • Proteins make up 6–8% of the blood. They are about equally divided between serum albumin and a great variety of serum globulins. After blood is withdrawn from a vein and allowed to clot, the clot slowly shrinks. As it does so, a clear fluid called serum is squeezed out. Thus: Serum is blood plasma without fibrinogen and other clotting factors.

Serum Proteins

•

Serum albumin

– – is made in the liver binds many small molecules for transport through the blood – helps maintain the osmotic pressure of the blood The other proteins are the various serum globulins (& fibrinogen)

Serum Proteins

• •

Serum globulin

They migrate in the order – – – alpha globulins (e.g., the proteins that transport thyroxine and retinol [vitamin A]) beta globulins (e.g., the iron-transporting protein transferrin) gamma globulins. • Gamma globulins are the least negatively-charged serum proteins. (They are so weakly charged, in fact, that some are swept in the flow of buffer back toward the negative electrode.) • Most antibodies are gamma globulins. Therefore gamma globulins become more abundant following infections or immunizations .

• •

Serum Lipids

Because of their relationship to cardiovascular disease, the analysis of serum lipids has become an important health measure. The table shows the range of typical values as well as the values above (or below) which the subject may be at increased risk of developing atherosclerosis .

LIPID

Cholesterol (total) LDL cholesterol LDL cholesterol HDL cholesterol Triglycerides

Typical values (mg/dl)

170 –210 60 –140 60 –140 35 –85 40 –160

Desirable (mg/dl)

<200 <100 <100 >40 <160 68

• Total cholesterol is the sum of – HDL cholesterol – LDL cholesterol and – 20% of the triglyceride value • Note that – high LDL values are bad, but – high HDL values are good.

• Using the various values, one can calculate a cardiac risk ratio = total cholesterol divided by HDL cholesterol • A cardiac risk ratio greater than 7 is considered a warning. 69

Nutritional disorders

   

Iron deficiency anemia Iron loading Pernicious anemia Vit K deficiency

  

Congenital disorders: Thallasemias Sickle cell anemia Hemophilia Secondary disorders



Urinary system:



Erythrocytosis



Immune problems:



Hemolytic disease of the newborn Blood disorders Tumors

  

Leukemia Myeloid Lymphoid Trauma



Hemorrhagic anemia



Aplastic anemia Infection

      Bacteremia Viremia Septicemia Puerperal fever Malaria Hemolytic anemia

Degenerative disorders:



Excessive coagulation

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• • •

Blood Transfusions

"whole blood“ were transfused directly into patients (e.g., to replace blood lost by trauma or during surgery). Most were further fractionated into components, including: – RBCs. When refrigerated these can be used for up to 42 days. – platelets. These must be stored at room temperature and thus can be saved for only 5 days. – plasma. This can be frozen and stored for up to a year. 71

Ensuring the safety of donated blood

• • A variety of infectious agents can be present in blood. – viruses (e.g., HIV-1 , hepatitis B and C, HTLV , West Nile virus – bacteria like the spirochete of syphilis – protozoans like the agents of malaria and babesiosis – prions (e.g., the agent of variant Crueutzfeldt-Jakob disease ) • and could be transmitted to recipients. To minimize these risks, – donors are questioned about their possible exposure to these agents; – each unit of blood is tested for a variety of infectious agents . 72

• Most of these tests are performed with enzyme immunoassays (EIA) and detect antibodies against the agents. However, it takes a period of time for the immune system to produce antibodies following infection, and during this period ("window"), infectious virus is present in the blood. For this reason, blood is now also checked for the presence of the RNA of these RNA viruses: – – HIV-1 hepatitis C – West Nile virus – by the so-called nucleic acid-amplification test (NAT).