Venules

Venules are small blood vessels in the microcirculation that connect capillary beds to veins.

A venule is a small blood vessel in the microcirculation that allows deoxygenated blood to return from capillary beds to larger blood vessels called veins. Venules range from 8 to 100μm in diameter and are formed when capillaries come together. Many venules unite to form a vein.

Venule walls have three layers: an inner endothelium composed of squamous endothelial cells that act as a membrane, a middle layer of muscle and elastic tissue, and an outer layer of fibrous connective tissue. The middle layer is poorly developed so that venules have thinner walls than arterioles. Venules are extremely porous so that fluid and blood cells can move easily from the bloodstream through their walls.

In contrast to regular venules, high-endothelial venules (HEV) are specialized post-capillary venous swellings. They are characterized by plump endothelial cells as opposed to the usual thinner endothelial cells found in regular venues. HEVs enable lymphocytes (white blood cells) circulating in the blood to directly enter a lymph node by crossing through the HEV.

Veins

Veins are blood vessels that carry blood from tissues and organs back to the heart; they have thin walls and one-way valves.

Veins are blood vessels that carry blood towards the heart. Most carry deoxygenated blood from the tissues back to the heart, but the pulmonary and umbilical veins both carry oxygenated blood to the heart. The difference between veins and arteries is the direction of blood flow (out of the heart through arteries, back to the heart through veins), not their oxygen content. Veins differ from arteries in structure and function. For example, arteries are more muscular than veins, veins are often closer to the skin, and veins contain valves to help keep blood flowing toward the heart, while arteries do not have valves and carry blood away from the heart. The precise location of veins is much more variable than that of arteries since veins often display anatomical variation from person to person.

Veins are also called capacitance vessels because they contain 60% of the body’s blood volume. In the systemic circulation, oxygenated blood is pumped by the left ventricle through the arteries to the muscles and organs of the body, where its nutrients and gases are exchanged at capillaries. The blood then enters venules, then veins filled with cellular waste and carbon dioxide. The deoxygenated blood is taken by veins to the right atrium of the heart, which transfers the blood to the right ventricle, where it is then pumped through the pulmonary arteries to the lungs. In pulmonary circulation the veins return oxygenated blood from the lungs to the left atrium, which empties into the left ventricle, completing the cycle of blood circulation.

Mechanisms to Return Blood

The return of blood to the heart is assisted by the action of the skeletal-muscle pump and by the thoracic pump action of breathing during respiration. As muscles move, they squeeze the veins that run through them. Veins contain a series of one-way valves. As the vein is squeezed, it pushes blood through the valves, which then close to prevent backflow. Standing or sitting for prolonged periods can cause low venous return from venous pooling. In venous pooling, the smooth muscles surrounding the veins become slack and the veins fill with the majority of the blood in the body, keeping blood away from the brain, which can cause unconsciousness.

Although most veins take the blood back to the heart, portal veins carry blood between capillary beds. For example, the hepatic portal vein takes blood from the capillary beds in the digestive tract and transports it to the capillary beds in the liver. The blood is then drained into the gastrointestinal tract and spleen, where it is taken up by the hepatic veins and blood is taken back into the heart. Since this is an important function in mammals, damage to the hepatic portal vein can be dangerous. Blood clotting in the hepatic portal vein can cause portal hypertension, which results in a decrease of blood fluid to the liver.

Vein Classification

Veins are classified in a number of ways, including superficial vs. deep, pulmonary vs. systemic, and large vs. small:

• Superficial veins: Superficial veins are close to the surface of the body and have no corresponding arteries.
• Deep veins: Deep veins are deeper in the body and have corresponding arteries.
• Communicating veins: Communicating veins (or perforator veins) directly connect superficial veins to deep veins.
• Pulmonary veins: The pulmonary veins deliver oxygenated blood from the lungs to the heart.
• Systemic veins: Systemic veins drain the tissues of the body and deliver deoxygenated blood to the heart.

Artery Function

Arteries are high-pressure blood vessels that carry oxygenated blood away from the heart to all other tissues and organs.

Arteries are blood vessels that carry blood away from the heart under pressure. This blood is usually oxygenated, with the exception of that in the pulmonary artery, which carries deoxygenated blood to the lungs.

As with veins, arteries are comprised of three layers: the tunicae intima, media, and external. In arteries, the tunica media, which contains smooth muscle cells and elastic tissue, is thicker than that of veins so it can modulate vessel caliber and thus control and maintain blood pressure.

Arterial pressure varies between the peak pressure during heart contraction, called the systolic pressure, and the minimum or diastolic pressure between contractions, when the heart expands and refills. This pressure variation within the artery produces the observable pulse that reflects heart activity. The pressure in the arterial system decreases steadily, highest in the aorta and lowest in the venous system, as blood approaches the heart after delivery of oxygen to tissues in the systemic circulation.

Arteries of the systemic circulation can be subdivided into muscular or elastic types according to the relative compositions of elastic and muscle tissue in their tunica media. Larger arteries are typically elastic and smaller arteries are more likely to be muscular. These arteries deliver blood to the arterioles, which in turn deliver blood to the capillary networks associated with the body’s tissues.

Elastic Arteries

An elastic or conducting artery has a large number of collagen and elastin filaments in the tunica media.

Elastic arteries contain larger numbers of collagen and elastin filaments in their tunica media than muscular arteries do, giving them the ability to stretch in response to each pulse.

Elastic arteries include the largest arteries in the body, those closest to the heart, and give rise to the smaller muscular arteries. The pulmonary arteries, the aorta, and its branches together comprise the body’s system of elastic arteries. In these large arteries, the amount of elastic tissue is considerable and the smooth muscle fiber cells are arranged in 5 to 7 layers in both circular and longitudinal directions.

The aorta: The aorta makes up most of the elastic arteries in the body.

Arterial elasticity gives rise to the Windkessel effect, which through passive contraction after expansion helps to maintain relatively constant pressure in the arteries despite the pulsating nature of the blood flow from the heart.

The Aorta

Due to its position as the first part of the systemic circulatory system closest to the heart and the resultant high pressures it will experience, the aorta is perhaps the most elastic artery, featuring an incredibly thick tunica media-rich in elastic filaments. The aorta is so thick that it requires its own capillary network to supply it with sufficient oxygen and nutrients to function, the vasa vasorum.

When the left ventricle contracts to force blood into the aorta, the aorta expands. This stretching generates the potential energy that will help maintain blood pressure during diastole when the aorta contracts passively. Additionally, the elastic recoil helps conserve the energy from the pumping heart and smooth the flow of blood around the body through the Windkessel effect.

Muscular Arteries

Distributing arteries are medium-sized arteries that draw blood from an elastic artery and branch into resistance vessels.

Splenic Artery: Transverse section of the human spleen showing the distribution of the splenic artery and its branches

Muscular or distributing arteries are medium-sized arteries that draw blood from an elastic artery and branch into resistance vessels, including small arteries and arterioles. In contrast to the mechanism elastic arteries use to store and dissipate the energy generated by the heart’s contraction, muscular arteries contain layers of smooth muscle providing allowing for involuntary control of vessel caliber and thus control of blood flow. Muscular arteries can be identified by the well-defined elastic lamina that lies between the tunica intima and media.

The splenic artery (lienal artery), the blood vessel that supplies oxygenated blood to the spleen, is an example of a muscular artery. It branches from the celiac artery and follows a course superior to the pancreas. The splenic artery branches off to the stomach and pancreas before reaching the spleen and gives rise to arterioles that directly supply capillaries of these organs.

Anastomoses

A circulatory anastomosis is a connection or looped interaction between two blood vessels.

An anastomosis refers to any joint between two vessels. Circulatory anastomoses are named based on the vessels they join: two arteries (arterio-arterial anastomosis), two veins (veno-venous anastomosis), or between an artery and a vein (arterio-venous anastomosis).

Anastomoses: The blood vessels of the rectum and anus, showing the distribution and anastomosis on the posterior surface near the termination of the gut.

Anastomoses between arteries and anastomoses between veins result in a multitude of arteries and veins serving the same volume of tissue. Such anastomoses occur normally in the body in the circulatory system, serving as backup routes for blood to flow if one link is blocked or otherwise compromised, but may also occur pathologically.

Examples of Anastomoses

Arterio-arterial anastomoses include actual joins (e.g. palmar arch, plantar arch) and potential ones, which may only function if the normal vessel is damaged or blocked (e.g. coronary arteries and cortical branch of cerebral arteries). Important examples include:

• The circle of Willis in the brain.
  The arrangement of the brain’s arteries into the circle of Willis creates redundancies for cerebral circulation. If one part of the circle becomes blocked or narrowed or one of the arteries supplying the circle is blocked or narrowed, blood flow from the other blood vessels can often preserve the cerebral perfusion well enough to maintain function.
• Joint anastomoses. Almost all joints receive anastomotic blood supply from more than one source. Examples include the knee and geniculate arteries, shoulder and circumflex humeral, and hip and circumflex iliac.
• Coronary artery anastomoses. The coronary arteries are functionally ended arteries, so these meetings are referred to as anatomical anastomosis, which lacks function. As blockage of one coronary artery generally results in the death of the heart tissue due to lack of sufficient blood supply from the other branch, when two arteries or their branches join, the area of the myocardium receives a dual blood supply. If one coronary artery is obstructed by an atheroma, a degradation of the arterial walls, the second artery is still able to supply oxygenated blood to the myocardium. However, this can only occur if the atheroma progresses slowly, giving the anastomosis time to form.

Pathological anastomoses result from trauma or disease and are usually referred to as fistulae. They can be very severe if they result in the bypassing of key tissues by the circulatory system.

Arterioles

An arteriole is a small-diameter blood vessel in the microcirculation system that branches out from an artery and leads to capillaries.

An arteriole is a small-diameter blood vessel that forms part of the microcirculation that extends from an artery and leads to capillaries.

Microcirculation involves the flow of blood in the smallest blood vessels, including arterioles, capillaries, and venules.

Arterioles have muscular walls that usually consist of one or two layers of smooth muscle. They are the primary site of vascular resistance. This reduces the pressure and velocity of blood flow to enable gas and nutrient exchange to occur within the capillaries. Arterioles are innervated and also respond to various circulating hormones and other factors such as pH in order to regulate their caliber, thus modulating the amount of blood flow into the capillary network and tissues.

Capillaries

Capillaries, the smallest blood vessels in the body, are part of microcirculation.

Capillaries, which form part of the micro-circulation, are the smallest of the body’s blood vessels at between 5-10
μm in diameter with the endothelial vessel wall of only one cell thick. They are surrounded by a thin basal lamina of connective tissue.

Capillary Function

Capillaries form a network through body tissues that connect arterioles and venules and facilitates the exchange of water, oxygen, carbon dioxide, and many other nutrients and waste substances between the blood and surrounding tissues.
The thin wall of the capillary and close association with its resident tissue allow for gas and lipophilic molecules to pass through without the need for special transport mechanisms. This allows bidirectional diffusion depending on osmotic gradients.

Formation of New Capillaries

During embryological development, new capillaries are formed by vasculogenesis, the process of blood vessel formation occurring by de novo production of endothelial cells and their formation into vascular tubes. The term angiogenesis denotes the formation of new capillaries from pre-existing blood vessels.

The Capillary Bed

Capillaries do not function independently. The capillary bed is an interwoven network of capillaries that supplies an organ. The more metabolically active the cells, the more capillaries required to supply nutrients and carry away waste products.

A capillary bed can consist of two types of vessels: true capillaries, which branch mainly from arterioles and provide exchange between cells and the circulation, and vascular shunts, short vessels that directly connect arterioles and venules at opposite ends of the bed, allowing for bypass.

Types of Capillaries

There are three main types of capillaries:

• Continuous: Endothelial cells provide an uninterrupted lining, only allowing small molecules like water and ions to diffuse through tight junctions. This leaves gaps of unjoined membrane called intercellular clefts.
• Fenestrated: Fenestrated capillaries have pores in the endothelial cells (60-80 nanometers in diameter) that are spanned by a diaphragm of radially oriented fibrils. They allow small molecules and limited amounts of protein to diffuse.
• Sinusoidal: Sinusoidal capillaries are a special type of fenestrated capillaries that have larger openings (30–40 μm in diameter) in the endothelium. These types of blood vessels allow red and white blood cells (7.5μm–25μm diameter) and various serum proteins to pass using a process aided by a discontinuous basal lamina. Sinusoid blood vessels are primarily located in the bone marrow, lymph nodes, and adrenal gland. Some sinusoids are special in that they do not have tight junctions between cells. These are called discontinuous sinusoidal capillaries, present in the liver and spleen where the greater movement of cells and materials is necessary.

Control of Flow

Capillary beds may control blood flow via autoregulation. This allows an organ to maintain constant flow despite a change in central blood pressure. This is achieved by the myogenic response and by tubuloglomerular feedback in the kidney. When blood pressure increases, the arterioles that lead to the capillary bed are stretched and subsequently constrict to counteract the increased tendency for high pressure to increase blood flow. In the lungs, special mechanisms have been adapted to meet the needs of the increased necessity of blood flow during exercise. When heart rate increases and more blood must flow through the lungs, capillaries are recruited and are distended to make room for increased blood flow while resistance decreases.

Artery Function

Arteries are high-pressure blood vessels that carry oxygenated blood away from the heart to all other tissues and organs.

Arteries are blood vessels that carry blood away from the heart under pressure. This blood is usually oxygenated, with the exception of that in the pulmonary artery, which carries deoxygenated blood to the lungs.

As with veins, arteries are comprised of three layers: the tunicae intima, media, and external. In arteries, the tunica media, which contains smooth muscle cells and elastic tissue, is thicker than that of veins so it can modulate vessel caliber and thus control and maintain blood pressure.

Arterial pressure varies between the peak pressure during heart contraction, called the systolic pressure, and the minimum or diastolic pressure between contractions, when the heart expands and refills. This pressure variation within the artery produces the observable pulse that reflects heart activity. The pressure in the arterial system decreases steadily, highest in the aorta and lowest in the venous system, as blood approaches the heart after delivery of oxygen to tissues in the systemic circulation.

Arteries of the systemic circulation can be subdivided into muscular or elastic types according to the relative compositions of elastic and muscle tissue in their tunica media. Larger arteries are typically elastic and smaller arteries are more likely to be muscular. These arteries deliver blood to the arterioles, which in turn deliver blood to the capillary networks associated with the body’s tissues.

Elastic Arteries

An elastic or conducting artery has a large number of collagen and elastin filaments in the tunica media.

Elastic arteries contain larger numbers of collagen and elastin filaments in their tunica media than muscular arteries do, giving them the ability to stretch in response to each pulse.

Elastic arteries include the largest arteries in the body, those closest to the heart, and give rise to the smaller muscular arteries. The pulmonary arteries, the aorta, and its branches together comprise the body’s system of elastic arteries. In these large arteries, the amount of elastic tissue is considerable and the smooth muscle fiber cells are arranged in 5 to 7 layers in both circular and longitudinal directions.

The aorta: The aorta makes up most of the elastic arteries in the body.

Arterial elasticity gives rise to the Windkessel effect, which through passive contraction after expansion helps to maintain relatively constant pressure in the arteries despite the pulsating nature of the blood flow from the heart.

The Aorta

Due to its position as the first part of the systemic circulatory system closest to the heart and the resultant high pressures it will experience, the aorta is perhaps the most elastic artery, featuring an incredibly thick tunica media-rich in elastic filaments. The aorta is so thick that it requires its own capillary network to supply it with sufficient oxygen and nutrients to function, the vasa vasorum.

When the left ventricle contracts to force blood into the aorta, the aorta expands. This stretching generates the potential energy that will help maintain blood pressure during diastole when the aorta contracts passively. Additionally, the elastic recoil helps conserve the energy from the pumping heart and smooth the flow of blood around the body through the Windkessel effect.

Muscular Arteries

Distributing arteries are medium-sized arteries that draw blood from an elastic artery and branch into resistance vessels.

Splenic Artery: Transverse section of the human spleen showing the distribution of the splenic artery and its branches

Muscular or distributing arteries are medium-sized arteries that draw blood from an elastic artery and branch into resistance vessels, including small arteries and arterioles. In contrast to the mechanism elastic arteries use to store and dissipate the energy generated by the heart’s contraction, muscular arteries contain layers of smooth muscle providing allowing for involuntary control of vessel caliber and thus control of blood flow. Muscular arteries can be identified by the well-defined elastic lamina that lies between the tunica intima and media.

The splenic artery (lienal artery), the blood vessel that supplies oxygenated blood to the spleen, is an example of a muscular artery. It branches from the celiac artery and follows a course superior to the pancreas. The splenic artery branches off to the stomach and pancreas before reaching the spleen and gives rise to arterioles that directly supply capillaries of these organs.

Anastomoses

A circulatory anastomosis is a connection or looped interaction between two blood vessels.

An anastomosis refers to any joint between two vessels. Circulatory anastomoses are named based on the vessels they join: two arteries (arterio-arterial anastomosis), two veins (veno-venous anastomosis), or between an artery and a vein (arterio-venous anastomosis).

Anastomoses: The blood vessels of the rectum and anus, showing the distribution and anastomosis on the posterior surface near the termination of the gut.

Anastomoses between arteries and anastomoses between veins result in a multitude of arteries and veins serving the same volume of tissue. Such anastomoses occur normally in the body in the circulatory system, serving as backup routes for blood to flow if one link is blocked or otherwise compromised, but may also occur pathologically.

Examples of Anastomoses

Arterio-arterial anastomoses include actual joins (e.g. palmar arch, plantar arch) and potential ones, which may only function if the normal vessel is damaged or blocked (e.g. coronary arteries and cortical branch of cerebral arteries). Important examples include:

• The circle of Willis in the brain.
  The arrangement of the brain’s arteries into the circle of Willis creates redundancies for cerebral circulation. If one part of the circle becomes blocked or narrowed or one of the arteries supplying the circle is blocked or narrowed, blood flow from the other blood vessels can often preserve the cerebral perfusion well enough to maintain function.
• Joint anastomoses. Almost all joints receive anastomotic blood supply from more than one source. Examples include the knee and geniculate arteries, shoulder and circumflex humeral, and hip and circumflex iliac.
• Coronary artery anastomoses. The coronary arteries are functionally ended arteries, so these meetings are referred to as anatomical anastomosis, which lacks function. As blockage of one coronary artery generally results in the death of the heart tissue due to lack of sufficient blood supply from the other branch, when two arteries or their branches join, the area of the myocardium receives a dual blood supply. If one coronary artery is obstructed by an atheroma, a degradation of the arterial walls, the second artery is still able to supply oxygenated blood to the myocardium. However, this can only occur if the atheroma progresses slowly, giving the anastomosis time to form.

Pathological anastomoses result from trauma or disease and are usually referred to as fistulae. They can be very severe if they result in the bypassing of key tissues by the circulatory system.

Arterioles

An arteriole is a small-diameter blood vessel in the microcirculation system that branches out from an artery and leads to capillaries.

An arteriole is a small-diameter blood vessel that forms part of the microcirculation that extends from an artery and leads to capillaries.

Microcirculation involves the flow of blood in the smallest blood vessels, including arterioles, capillaries, and venules.

Arterioles have muscular walls that usually consist of one or two layers of smooth muscle. They are the primary site of vascular resistance. This reduces the pressure and velocity of blood flow to enable gas and nutrient exchange to occur within the capillaries. Arterioles are innervated and also respond to various circulating hormones and other factors such as pH in order to regulate their caliber, thus modulating the amount of blood flow into the capillary network and tissues.

Capillaries

Capillaries, the smallest blood vessels in the body, are part of microcirculation.

Capillaries, which form part of the micro-circulation, are the smallest of the body’s blood vessels at between 5-10
μm in diameter with the endothelial vessel wall of only one cell thick. They are surrounded by a thin basal lamina of connective tissue.

Capillary Function

Capillaries form a network through body tissues that connect arterioles and venules and facilitates the exchange of water, oxygen, carbon dioxide, and many other nutrients and waste substances between the blood and surrounding tissues.
The thin wall of the capillary and close association with its resident tissue allow for gas and lipophilic molecules to pass through without the need for special transport mechanisms. This allows bidirectional diffusion depending on osmotic gradients.

Formation of New Capillaries

During embryological development, new capillaries are formed by vasculogenesis, the process of blood vessel formation occurring by de novo production of endothelial cells and their formation into vascular tubes. The term angiogenesis denotes the formation of new capillaries from pre-existing blood vessels.

The Capillary Bed

Capillaries do not function independently. The capillary bed is an interwoven network of capillaries that supplies an organ. The more metabolically active the cells, the more capillaries required to supply nutrients and carry away waste products.

A capillary bed can consist of two types of vessels: true capillaries, which branch mainly from arterioles and provide exchange between cells and the circulation, and vascular shunts, short vessels that directly connect arterioles and venules at opposite ends of the bed, allowing for bypass.

Types of Capillaries

There are three main types of capillaries:

• Continuous: Endothelial cells provide an uninterrupted lining, only allowing small molecules like water and ions to diffuse through tight junctions. This leaves gaps of unjoined membrane called intercellular clefts.
• Fenestrated: Fenestrated capillaries have pores in the endothelial cells (60-80 nanometers in diameter) that are spanned by a diaphragm of radially oriented fibrils. They allow small molecules and limited amounts of protein to diffuse.
• Sinusoidal: Sinusoidal capillaries are a special type of fenestrated capillaries that have larger openings (30–40 μm in diameter) in the endothelium. These types of blood vessels allow red and white blood cells (7.5μm–25μm diameter) and various serum proteins to pass using a process aided by a discontinuous basal lamina. Sinusoid blood vessels are primarily located in the bone marrow, lymph nodes, and adrenal gland. Some sinusoids are special in that they do not have tight junctions between cells. These are called discontinuous sinusoidal capillaries, present in the liver and spleen where the greater movement of cells and materials is necessary.

Control of Flow

Capillary beds may control blood flow via autoregulation. This allows an organ to maintain constant flow despite a change in central blood pressure. This is achieved by the myogenic response and by tubuloglomerular feedback in the kidney. When blood pressure increases, the arterioles that lead to the capillary bed are stretched and subsequently constrict to counteract the increased tendency for high pressure to increase blood flow. In the lungs, special mechanisms have been adapted to meet the needs of the increased necessity of blood flow during exercise. When heart rate increases and more blood must flow through the lungs, capillaries are recruited and are distended to make room for increased blood flow while resistance decreases.

Anatomy of the Heart

The heart is an organ responsible for pumping blood through the blood vessels using rhythmic contractions of cardiac muscle.

The human heart is the pump for the circulatory system, and along with the circulatory system is considered to be an organ of the cardiovascular system. It consists of four chambers and pumps blood through both systemic and pulmonary circulation to enable gas exchange and tissue oxygenation. The heart is located in the thoracic cavity between the lungs and protected by the rib cage.

Structure of the Heart

The heart consists of four chambers separated into two sides. Each side contains an atrium that receives blood into the heart and flows it into a ventricle, which pumps the blood out of the heart. The atria and ventricle on each side of the heart are linked together by valves that prevent the backflow of blood. The wall that separates the left and right sides of the heart is called the septum.

The left heart deals with systemic circulation, while the right heart deals with pulmonary circulation. The left side of the heart receives oxygenated blood from the pulmonary vein and pumps it into the aorta, while the right side of the heart receives deoxygenated blood from the vena cava and pumps it into the pulmonary vein. The pulmonary vein and aorta also have valves connecting them to their respective ventricle.

The heart has its own self-sustaining conduction system that sends nervous impulses to cardiac tissue. The sinoatrial (SA) and atrioventricular (AV) nodes are bundles of nerve fibers that form this conduction system. They are located in the left atrial wall of the heart and send nerve impulses to a large, highly specialized set of nerves called the Purkinje fibers, which in turn send those nerve impulses to the cardiac muscle tissue. These nodes can send impulses to the heart without central nervous system stimulation but may be influenced by nervous stimulation to alter heart rate. The heart also has its own blood supply, the cardiac arteries that provide tissue oxygenation to the heart as the blood within the heart are not used for oxygenation by the heart.

Cardiac Histology

The heart is enclosed in a double-walled protective membrane called the pericardium, which is a mesothelium tissue of the thoracic cavity. The double membrane of the pericardium contains pericardial fluid which nourishes the heart and prevents shock. This composite sac protects the heart, anchors it to surrounding structures, and prevents the heart from overfilling with blood.

The wall of the heart is composed of three layers of different tissues. The outer layer is called the epicardium, or visceral pericardium since it is also the inner wall of the pericardium. The middle layer of the heart, the myocardium, and contains specialized cardiac muscle tissue responsible for contraction. Cardiac muscle tissue is distinct from skeletal or smooth muscle because it pumps involuntarily based on conduction from the AV and SA nodes. The inner layer is called the endocardium and is in contact with the blood that the heart pumps. It also merges with the inner lining of blood vessels and covers heart valves. Cardiac tissue is permanent tissue that does not heal or regenerate when damaged. As a result, is prone to scarring and enlargement due to mechanical stress and injury.

 

The Mammalian Heart: The position of valves ensures proper directional flow of blood through the cardiac interior. Note the difference in the thickness of the muscled walls of the atrium and the left and right ventricle.

Pericardium

The pericardium is a thick, membranous, fluid-filled sac which encloses, protects, and nourishes the heart.

The pericardium is the thick, membranous, fluid-filled sac that surrounds the heart and the roots of the vessels that enter and leave this vital organ, functioning as a protective membrane. The pericardium is one of the mesothelium tissues of the thoracic cavity, along with the pleura which cover the lungs. The pericardium is composed of two layers, an outer fibrous pericardium and an inner serous pericardium.

 

Membranes of the Thoracic Cavity: A transverse section of the thorax, showing the contents of the middle and the posterior mediastinum. The pleural and pericardial cavities are exaggerated since normally there is no space between parietal and visceral pleura and between pericardium and heart.

Fibrous Pericardium

The fibrous pericardium is the outer layer of the pericardium. It is composed of dense connective tissue which anchors the heart to the mediastinum of the chest wall. It prevents the heart from overfilling with blood and protects it from nearby infections by completely separating it from the rest of the thoracic cavity. It is continuous with the outer fibrous layer of the neighboring great blood vessels.

Serous Pericardium

The serous pericardium, the inner layer of the pericardium, is composed of two different layers. The outer layer, the parietal layer, is completely adhered to the fibrous pericardium. The inner layer is known as the visceral layer, which covers and protects the great vessels and heart. The space between the parietal and visceral layers is called the pericardial cavity.

The visceral layer is referred to as the epicardium in the areas where it is in direct contact with the heart. The space between these two serous layers, the parietal and the visceral, is the pericardial cavity, which contains pericardial fluid. The serous pericardium, with its two membranes and the fluid-filled pericardial cavity, provides protection to the heart and a lubricated sliding surface within which the heart can move in response to its own contractions and to the movement of adjacent structures such as the diaphragm and the lungs.

Function of the Pericardium

The pericardium is important because it protects the heart from trauma, shock, stress, and even infections from the nearby lungs. It supports the heart and anchors it to the mediastinum so it doesn’t move within the body. The pericardium lubricates the heart and prevents it from becoming too large if blood volume is overloaded (though it will not prevent chronic heart enlargement).

Despite these functions, pericardium is still vulnerable to problems of its own. Pericarditis is the term for inflammation in the pericardium, typically due to infection. Pericarditis is often a severe disease because it can constrict and apply pressure on the heart and work against its normal function. Pericarditis comes in many types depending on which tissue layer is infected.

Layers of the Heart Walls

The heart wall is comprised of three layers: the outer epicardium, the middle myocardium, and the inner endocardium.

The heart wall is comprised of three layers, the epicardium (outer), myocardium (middle), and endocardium (inner). These tissue layers are highly specialized and perform different functions. During ventricular contraction, the wave of depolarization from the SA and AV nodes moves from within the endocardial wall through the myocardial layer to the epicardial surface of the heart.

Epicardium

 

The Heart Wall: The wall of the heart is composed of three layers, the thin outer epicardium, the thick middle myocardium, and the very thin inner endocardium. The dark area on the heart wall is scarring from a previous myocardial infarction (heart attack).

The outer layer of the heart wall is the epicardium. The epicardium refers to both the outer layer of the heart and the inner layer of the serous visceral pericardium, which is attached to the outer wall of the heart. The epicardium is a thin layer of elastic connective tissue and fat that serves as an additional layer of protection from trauma or friction for the heart under the pericardium. This layer contains the coronary blood vessels, which oxygenate the tissues of the heart with a blood supply from the coronary arteries.

Myocardium

The middle layer of the heart wall is the myocardium—the muscle tissue of the heart and the thickest layer of the heart wall. It is composed of cardiac muscle cells or cardiomyocytes. Cardiomyocytes are specialized muscle cells that contract like other muscle cells but differ in shape. Compared to skeletal muscle cells, cardiac muscle cells are shorter and have fewer nuclei. Cardiac muscle tissue is also striated (forming protein bands) and contains tubules and gap junctions, unlike skeletal muscle tissue. Due to their continuous rhythmic contraction, cardiomyocytes require a dedicated blood supply to deliver oxygen and nutrients and remove waste products such as carbon dioxide from the cardiac muscle tissue. This blood supply is provided by the coronary arteries.

Endocardium

The inner layer of the heart wall is the endocardium, composed of endothelial cells that provide a smooth, elastic, non-adherent surface for blood collection and pumping. The endocardium may regulate metabolic waste removal from heart tissues and act as a barrier between the blood and the heart muscle, thus controlling the composition of the extracellular fluid in which the cardiomyocytes bathe. This in turn can affect the contractility of the heart.

This issue also covers the valves of the heart and is histologically continuous with the vascular endothelium of the major blood vessels entering and leaving the heart. The Purkinje fibers are located just beneath the endocardium and send nervous impulses from the SA and AV nodes outside of the heart into the myocardial tissues.

The endocardium can become infected, a serious inflammatory condition called infective endocarditis. This and other potential problems with the endocardium may damage the valves and impair the normal flow of blood through the heart.

Chambers of the Heart

The heart has four chambers. The two atria receive blood into the heart and the two ventricles pump blood into circulation.

The heart is the complex pump of the circulatory system, pumping blood throughout the body for the purposes of tissue oxygenation and gas exchange. The heart has four chambers through which blood flows: two sets of each type of chamber (atria and ventricles), one per side, each with distinct functions. The left side of the heart deals with systemic circulation while the right side of the heart deals with pulmonary circulation.

The Atria

The atria are chambers in which blood enters the heart. They are located on the anterior end of the heart, with one atrium on each side. The right atrium receives deoxygenated blood from systemic circulation through the superior vena cava and inferior venae cavae. The left atrium receives oxygenated blood from pulmonary circulation through the left and right pulmonary veins.

Blood passively flows into the atria without passing through valves. The atria relax and dilate (expand) while they fill with blood in a process called atrial diastole. The atria and ventricles are separated by the mitral and tricuspid valves. The atria undergo atrial systole, a brief contraction of the atria that ejects blood from the atria through the valves and into the ventricles. The chordae tendinae are elastic tendons that attach to the valve from the ventricles and relax during atrial systole and ventricular diastole, but contract and close off the valve during ventricular systole.

One of the defining characteristics of the atria is that they do not impede venous flow into the heart. Atria has four essential characteristics that cause them to promote continuous venous flow:

• There are no atrial inlet valves to interrupt blood flow during atrial systole. The venous blood entering the heart has a very low pressure compared to arterial blood, and valves would require venous blood pressure to build up over a long period of time to enter the atria.
• The atrial systole contractions are incomplete and do not block flow from the veins through the atria into the ventricles. During atrial systole, blood not only empties from the atria to the ventricles, but continues to flow uninterrupted from the veins right through the atria into the ventricles.
• The atrial contractions are slight, preventing significant back pressure that would impede venous flow.
• The relaxation of the atria is coordinated to begin before the start of ventricular contraction, which also helps prevent the heart from beating too slowly.

Ventricles

The ventricles are located on the posterior end of the heart beneath their corresponding atrium. The right ventricle receives deoxygenated blood from the right atria and pumps it through the pulmonary vein and into the pulmonary circulation, which goes into the lungs for gas exchange. The left ventricle receives oxygenated blood from the left atria and pumps it through the aorta into the systemic circulation to supply the tissues of the body with oxygen.

The walls of the ventricles are thicker and stronger than those of the atria. The physiologic load on the ventricles, which pumps blood throughout the body and lungs, is much greater than the pressure generated by the atria to fill the ventricles. Further, the left ventricle has thicker walls than the right because it pumps blood throughout the body, while the right ventricle pumps only to the lungs, which is a much smaller volume of blood.

During ventricular diastole, the ventricles relax and fill with blood. During ventricular systole, the ventricles contract, pumping blood through the semi-lunar valves into the systemic circulation.

 

Structure of the heart: Structure diagram of a coronal section of the human heart from an anterior view. The two larger chambers are the ventricles.

Great Vessels of the Heart

Great vessels are the major vessels that directly carry blood into or out of the heart.

The human circulatory system is a double system, meaning there are two separate systems of blood flow: pulmonary circulation and systemic circulation. The adult human heart consists of two separate pumps, the right side (right atrium and ventricle,) which pumps deoxygenated blood into the pulmonary circulation, and the left side (left atrium and ventricle), which pumps oxygenated blood into the systemic circulation. Great vessels are the major vessels that carry blood into the heart and away from the heart to and from the pulmonary or systemic circuit. The great vessels collect and distribute blood across the body from numerous smaller vessels.

The Venae Cavae

 

The Systemic Circuit: The venae cavae and the aorta from the systemic circuit, which circulates blood to the head, extremities, and abdomen.

The superior and inferior vena cava are collectively called the venae cavae. The venae cavae, along with the aorta, are the great vessels involved in the systemic circulation. These veins return deoxygenated blood from the body into the heart, emptying it into the right atrium. The venae cavae are not separated from the right atrium by valves.

Superior Vena Cava

The superior vena cava is a large, short vein that carries deoxygenated blood from the upper half of the body to the right atrium. The right and left subclavian veins, jugular veins, and thyroid veins feed into the superior vena cava. The subclavian veins are significant because the thoracic lymphatic duct drains lymph fluid into the subclavian veins, making the superior vena cava a site of lymph fluid recirculation into the plasma. The superior vena cava begins above the heart.

Inferior Vena Cava

The inferior vena cava is the largest vein in the body and carries deoxygenated blood from the lower half of the body into the heart. The left and right common iliac veins converge to form the inferior vena cava at its lowest point. The inferior vena cava begins posterior to the abdominal cavity and travels to the heart next to the abdominal aorta. Along the way up the body from the iliac veins, the renal and suprarenal veins ( kidney and adrenal glands), lumbar veins (from the back), and hepatic veins (from the liver) all drain into the inferior vena cava.

The Aorta

The aorta is the largest of the arteries in systemic circulation. Blood is pumped from the left ventricle through the aortic valve into the aorta. The aorta is a highly elastic artery and is able to dilate and constrict in response to blood pressure and volume. When the left ventricle contracts to force blood through the aortic valve into the aorta, the aorta expands. This expansion provides potential energy to help maintain blood pressure during diastole, when the aorta passively contracts. Blood pressure is highest in the aorta and diminishes through circulation, reaching its lowest points at the end of venous circulation. The difference in pressure between the aorta and right atrium accounts for blood flow in the circulation, as blood flows from areas of high pressure to areas of low pressure.

Components of the Aorta

The aortic arch contains peripheral baroreceptors (pressure sensors) and chemoreceptors (chemical sensors) that relay information concerning blood pressure, blood pH, and carbon dioxide levels to the medulla oblongata of the brain. This information is processed by the brain and the autonomic nervous system mediates the homeostatic responses that involve feedback in the lungs and kidneys. The aorta extends around the heart and travels downward, diverging into the iliac arteries. The five components of the aorta are:

• The ascending aorta lies between the heart and the arch of the aorta. It breaks off into the aortic sinuses, some of which form the coronary arteries.
• The arch of the aorta is the peak of the aorta, which breaks off into the left carotid artery, brachiocephalic trunk, and the left subclavian artery.
• The descending aorta is the section from the arch of the aorta to the point where it divides into the common iliac arteries. It is subdivided into the thoracic and abdominal aorta.
• The thoracic aorta is the part of the descending aorta above the diaphragm. It branches off into the bronchial, mediastinal, esophageal, and phrenic arteries.
• The abdominal aorta is the part of the descending aorta below the diaphragm, which divides into the iliac arteries and branches into the renal and suprarenal arteries. This part of the aorta is vulnerable to bursting and hemorrhage (aneurysm) from persistently high blood pressure.

The Pulmonary Arteries

The pulmonary arteries carry deoxygenated blood from the right ventricle into the alveolar capillaries of the lungs to unload carbon dioxide and take up oxygen. These are the only arteries that carry deoxygenated blood, and are considered arteries because they carry blood away from the heart. The short, wide vessel branches into the left and right pulmonary arteries that deliver deoxygenated blood to the respective lungs. Blood first passes through the pulmonary valve as it is ejected into the pulmonary arteries.

 

Pulmonary circuit: Diagram of pulmonary circulation. Oxygen-rich blood is shown in red; oxygen-depleted blood in blue.

The Pulmonary Veins

The pulmonary veins carry oxygenated blood from the lungs to the left atrium of the heart. Despite carrying oxygenated blood, this great vessel is still considered a vein because it carries blood towards the heart. Four pulmonary veins enter the left atrium. The right pulmonary veins pass behind the right atrium and superior vena cava while the left pass in front of the descending thoracic aorta. The pulmonary arteries and veins are both considered part of pulmonary circulation.

Myocardial Thickness and Function

The myocardium (cardiac muscle) is the thickest section of the heart wall and contains cardiomyocytes, the contractile cells of the heart.

The myocardium, or cardiac muscle, is the thickest section of the heart wall and contains cardiomyocytes, the contractile cells of the heart. As a type of muscle tissue, the myocardium is unique among all other muscle tissues in the human body. The thickness of the myocardium determines the strength of the heart’s ability to pump blood.

Myocardial Histology

The structure of cardiac muscle shares some characteristics with skeletal muscle but has many distinctive features of its own. Cardiomyocytes are shorter than skeletal myocytes and have fewer nuclei. Each muscle fiber connects to the plasma membrane (sarcolemma) with distinctive tubules ( T-tubule ). At these T-tubules, the sarcolemma is studded with a large number of calcium channels which allow calcium ion exchange at a rate much faster than that of the neuromuscular junction in skeletal muscle. The flux of calcium ions into the muscle cells causes stimulates an action potential, which causes the cells to contract.

Cardiac muscle, like skeletal muscle, is comprised of sarcomeres, the basic, contractile units of muscle. Sarcomeres are composed of long, fibrous proteins that slide past each other when the muscles contract and relax. Two of the important proteins found in sarcomeres are myosin, which forms the thick filament, and actin, which forms the thin filament. Myosin has a long, fibrous tail and a globular head that binds to actin. The myosin head also binds to ATP, the source of energy for cellular metabolism, and is required for the cardiomyocytes to sustain themselves and function normally. Together, myosin and actin form myofibril filaments, the elongated, contractile threads found in muscle tissue. Cardiac muscle  and skeletal muscle both contain the protein myoglobin, which stores oxygen.

Cardiac muscle is adapted to be highly resistant to fatigue. Cardiomyocytes have a large number of mitochondria, enabling continuous aerobic respiration. Cardiac muscle also has a large blood supply relative to its size, which provides a continuous stream of nutrients and oxygen while providing ample removal of metabolic waste.

 

Cardiac Muscle: The tissue structure of cardiac muscle contains sarcomeres that are made of myofibrils with intercalated disks, that contain cardiomyocytes, and have many mitochondrial.

Myocardial Thickness

The myocardium has variable levels of thickness within the heart. Chambers of the heart with a thicker myocardium are able to pump blood with more pressure and force compared to chambers of the heart with a thinner myocardium. The myocardium is thinnest within the atria, as these chambers primarily fill through passive blood flow. The right ventricle myocardium is thicker than the atrial myocardium, as this muscle must pump all blood returning to the heart into the lungs for oxygenation. The myocardium is thickest in the left ventricle, as this chamber must create substantial pressure to pump blood into the aorta and throughout the systemic circulation.

The thickness of the myocardium may change in some individuals as a compensatory adaptation to disease, either thickening and becoming stiff or becoming thinner and flabby. Cardiac hypertrophy is a common result of hypertension (high blood pressure) in which the cells of the myocardium enlarge as an adaptive response to pumping against the higher pressure. Eventually, hypertrophy may become so severe that heart failure occurs when the heart becomes so stiff that it can no longer pump blood. A flabby heart is typically the result of myocardial infections, in which the heart muscle becomes so weak that it cannot efficiently pump blood, which also leads to heart failure.

 

Right Ventricular Hypertrophy: If the heart adapts to become too thick, it will not be able to pump blood as efficiently, and heart failure may occur.

Fibrous Skeleton of the Heart

The cardiac skeleton, also known as the heart’s fibrous skeleton, consists of dense connective tissue in the heart that separates the atria from the ventricles.

The cardiac skeleton, or fibrous skeleton of the heart, is the structure of dense connective tissue that separates the atria from the ventricles. The fibrous skeleton provides critical support for the heart and separates the flow of electrical impulses through the heart.

Fibrous Ring Structure

 

Fibrous Rings of the Heart: Transverse section of the heart showing the fibrous rings surrounding the valves.

The primary structure of the cardiac skeleton consists of four dense bands of tough elastic tissue called fibrous rings that encircle the bases of the heart valves. The fibrous skeleton is composed primarily of collagen, a protein found in every type of connective tissue in the human body. There are four fibrous rings:

• The aortic ring encircles the aortic valve. It provides support for the aortic valve so that it is open, yet does not have backflow.
• The pulmonary ring encircles the pulmonary valve. Similar to the aortic ring, it provides structural support for the pulmonary valve.
• The left fibrous ring encircles the bicuspid valve. This ring is the thickest and strongest of all the fibrous rings due to the thickness of the left ventricle, which requires more structural support than the other chambers of the heart. It also surrounds the coronary arteries and AV node.
• The right fibrous ring encircles the tricuspid valve. It also surrounds the coronary arteries and AV node.

The fibrous skeleton provides a great amount of structural and functional support for the valves of the heart by enabling them to stay open and provides a point of attachment for the valves to the wall of the heart.

Electrical Functions

The fibrous skeleton of the heart acts as an insulator for the flow of electrical current across the heart. It stops the flow of electricity between the different chambers of the heart so that electrical impulses do not flow directly between the atria and ventricles. The sinoatrial (SA) node lies on the top of the heart, while the AV node is located at the center of the fibrous skeleton, the only path by which electricity can flow through the heart.

This electrical separation is essential for cardiac function because electrical impulses flow from the top of the heart to the bottom of the heart. The separation allows the AV node and AV bundle to delay the wave of depolarization so that the atria can contract and assist in the ventricular filling before the ventricles themselves depolarize and contract. Without the fibrous skeleton of the heart, the heart’s ability to pump blood would be considerably less efficient since the ventricles would contract before filled to capacity. The fibrous skeleton of the heart also protects against cardiac arrhythmias.

Transfusions of Whole Blood

Whole blood refers to human blood transfusion from a standard blood donation.

Blood transfusions are a key therapeutic component to treating those with excessive blood loss from severe injury or surgery. Whole blood refers to blood drawn directly from the body from which none of the components, such as plasma or platelets, have been removed. The blood is typically combined with an anticoagulant during the collection process but is otherwise unprocessed. Whole blood may also be altered and processed for use in blood transfusion.

Blood Processing

Centrifuged Blood: Whole blood is a term used in transfusion medicine for human blood from a standard blood donation.

Plasma and Blood Volume Expanders

A volume expander is a type of intravenous therapy that provides a fluid replacement for the circulatory system.

When blood is lost, the greatest immediate need is to stop further blood loss, then lost volume must be replaced. Blood volume is directly proportional to the blood pressure in the body, and when both decrease the flow of blood to important tissues may be inhibited. The remaining red blood cells can still oxygenate body tissue. A volume expander is a type of intravenous therapy that provides blood volume for the circulatory system. It may be used for fluid replacement.

Blood Volume and Oxygen Transport

Normal human blood has a significant excess oxygen transport capability because not all of the hemoglobin molecules are loaded with oxygen under normal conditions. As long as pulmonary function is sufficient for gas exchange and there is enough blood volume to have sufficient blood pressure, very low hemoglobin levels will be enough to sustain the patient. Those with low hemoglobin content will not be able to tolerate situations where a greater amount of oxygen is required (exercise, for example) until their hemoglobin levels are restored.

The body has compensatory feedback mechanisms to deal with lower hemoglobin levels. For instance, the heart pumps more blood with each beat, which increases blood pressure. Blood pressure is detected by the renal system, which increases blood volume and blood pressure by excreting less water during blood filtration. As a result of partial pressure gradient changes, more oxygen is released to the tissues. These adaptations are so effective that if only half of the red blood cells remain, oxygen delivery will still be around 75% of normal. A patient at rest only uses 25% of the oxygen available in their blood. In extreme cases, patients have survived with a hemoglobin level of about 1/7 the normal (i.e. 2 g/dl), although levels this low are very dangerous.

When blood loss is significant, the red blood cell level ultimately drops to a level that is too low for adequate tissue oxygenation. This is marked by hypoxia and hypovolemic shock, a condition in which tissue oxygenation drops from a lack of blood volume and harmful compensatory mechanisms activate, causing more damage. In these situations, the only alternatives are blood transfusion, packed red blood cells, or oxygen therapy.

Types of Volume Expanders

Saline solution: A bag of saline. Saline can be used to increase blood volume when a blood transfusion is not possible.

There are two main types of volume expanders: crystalloids and colloids. Crystalloids are aqueous solutions of mineral salts or other water-soluble molecules. Colloids contain larger insoluble molecules, such as gelatin; blood itself is a colloid. There are also a few other volume expanders that may be used in certain situations:

• Colloids: These solutions preserve a high-colloid osmotic pressure (protein-exerted pressure) in the blood, while this parameter is decreased by crystalloids due to hemodilution. The higher osmotic pressure from colloids draws fluids inward, preventing it from leaking out into the tissues as easily, which increases intravascular blood volume.
• Crystalloids: The most commonly used crystalloid fluid is normal saline, a solution of sodium chloride at 0.9% concentration, which is close to the concentration in the blood (isotonic). Saline solution is administered intravenously (IV drips) and increases both intravascular and interstitial volume. They decrease osmotic pressure by diluting the blood.
• Dextrose Water: This solution contains dextrose, a form of glucose. It is given to patients who have dangerously low blood sugar levels (important for cellular metabolism) as well as low blood volume.

Another common volume expander includes hydroxyethyl starch (HES/HAES, common trade names: Hespan, Voluven) which is considered a colloid. An intravenous solution of hydroxyethyl starch is used to prevent shock following severe blood loss caused by trauma, surgery, or another problem. It increases the blood volume, allowing red blood cells to continue to deliver oxygen to the body. When tissue blood perfusion is maintained, shock is averted as the dangerous compensatory mechanisms of shock aren’t activated.

Blood Groups and Blood Types

Red blood cells have surface-expressed proteins that define the self/not-self nature of the cells.

Red blood cells have surface-expressed proteins that act as antigens, which are molecules that can illicit an immune system response. Red blood cells belong to different groups on the basis of the type of antigen that they express. Blood type determines compatibility for receiving blood transfusions from other people.

The ABO Blood Group System

If an individual is exposed to a blood group antigen (A or B) that is not recognized as self, the individual can become sensitized to that antigen. This will cause the immune system to make specific antibodies to a particular blood group antigen and form an immunological memory against that antigen. These antibodies can bind to antigens on the surface of transfused red blood cells (or other foreign tissue cells), often leading to destruction of the cells by recruitment of other components of the immune system.

Knowledge of an individual’s blood type is important to identify appropriate blood for transfusion or tissue for organ transplantation. There are four blood types that differ based on the antigen expressed by the red blood cell and by the type of associated antibody found in the plasma. The type of antigen determines which blood types that blood type may safely be donated to, while the type of antibody determines which types of antigen (and types of blood) will be rejected by the body.

• Blood group A individuals have the A antigen on the surface of their RBCs, and blood serum containing IgM antibodies against the B antigen. Therefore, a group A individual can only receive blood from individuals of groups A or O types and can donate blood to individuals of groups A or AB.
• Blood group B individuals have the B antigen on the surface of their RBCs, and blood serum containing IgM antibodies against the A antigen. Therefore, a group B individual can only receive blood from individuals of groups B or O and can donate blood to individuals of groups B or AB.
• Blood Group AB individuals have both A and B antigens on the surface of their RBCs, and their blood serum does not contain any antibodies against either A or B antigen. Therefore, an individual with type AB blood can receive blood from any group, but can only donate blood to another group AB individual. AB blood is also known as the “universal receiver.”
• Blood group O individuals do not have either A or B antigens on the surface of their RBCs, but their blood serum contains IgM antibodies against both A and B antigens. Therefore, a group O individual can only receive blood from a group O individual, but they can donate blood to individuals of any ABO blood group (i.e. A, B, O, or AB). O blood is also known as “universal donor.”

Blood types are inherited and represent genetic contributions from both parents. The gene that codes for blood type contain three alleles: IA and IB which give type A and B blood and are dominant, and I, which is recessive, and codes type O. Children will have blood types similar to their parents based on inheritance. The I allele is far more commonly expressed in the gene pool than IA and IB, which is why type O blood is the most common type despite being a recessive phenotype. Type AB is the rarest because it is the combination of less commonly expressed alleles, and is the result of codominance between IA and IB alleles.

Rhesus Factor

Many people also have the rhesus D (Rh) antigen expressed by their red blood cells. Those that have Rh antigens are positive for Rh, while those that don’t have it are Rh-negative (ie. type O+ is type O with rhesus, type A- is type A without rhesus). Rh-positive individuals do not have the antibodies for the Rh factor but can make them if exposed to Rh. Besides being a consideration for blood transfusion, parents who differ based on Rh status must be cautious to ensure that maternal antibodies do not destroy their child’s red blood cells during fetal development, which can cause hemolytic anemia.

Typing and Cross-Matching for Transfusions

Blood banks test donor blood to ensure recipient compatibility, reducing the risk of hemolytic reaction, renal failure, and death.

Transfusion medicine is extremely effective at treating those with severe blood loss. Transfusions are often a required component of major surgeries. Due to the different antigen blood types, blood must be cross-matched during processing to avoid potential complications.

The Cross-Matching Process

Much of the routine work of a blood bank involves testing blood from both donors and recipients to ensure that every recipient is given blood that is compatible and is as safe as possible. Several laboratory tests allow cross-matching of compatible blood between donor and recipient. Patients should ideally receive their own blood or type-specific blood products to minimize the chance of a transfusion reaction. Risks can be further reduced by cross-matching blood, but this process isn’t always performed if time is short and the need for transfusion has not been anticipated.

Agglutinated RBC: Red blood cells can agglutinate if the serum contains antibodies against the expressed proteins. In this image, the blood serum contains anti-A3 antibodies, which attack and agglutinate type A blood.

Cross-matching involves mixing a sample of the recipient’s serum with a sample of the donor’s red blood cells and checking if the mixture agglutinates, or forms clumps. These clumps are the result of antibodies binding the red blood cells together. If agglutination is not obvious by direct vision, blood bank technicians check for agglutination with a microscope. If agglutination occurs, that particular donor’s blood cannot be transfused to that particular recipient. In a blood bank, it is vital that all blood specimens are correctly identified, so labeling has been standardized using a barcode system known as ISBT 128. The blood group may be included on identification by military personnel in case they need an emergency blood transfusion.

Potential Transfusion Complications

If a patient receives blood during a transfusion that is not compatible with his or her blood type, severe problems can occur. Acute hemolytic transfusion reactions occur if donated blood cells are attacked by matching host antibodies. This can cause shock-like symptoms, such as fever, hypotension, and disseminated intravascular coagulation from immune system-mediated endothelial damage. Transfusion reactions are also associated with acute renal failure. Lung injury is common as well, due to pulmonary edema from fluid overload if plasma volume becomes too high or neutrophil activation during a transfusion reaction. If the donated blood is contaminated with bacteria, it may induce septic shock in the patient.

Transfusion adverse events

Negative reactions to receiving a blood transfusion are very rare. They are known as ‘transfusion adverse events’.

Most transfusion adverse events are mild – such as itching, fever, hives or rash – and can be treated easily. The most common adverse reaction to a blood transfusion is a mild fever, which occur in less than one in 1,000 transfusions. Most transfusion adverse events occur within 24 hours of a transfusion.

Severe reactions are very rare, but can be life-threatening. They need immediate treatment. A severe reaction may involve:

• breathing difficulties – which may be caused by severe allergic reaction (anaphylaxis), bacterial infection, red cell breakdown or transfusion-related acute lung injury (TRALI)
• high fever and shaking
• low blood pressure
• dark urine
• aches and pains.

If you experience any symptoms of a negative reaction to transfusion, let your health care team know immediately.

Complications

There are multiple complications of blood transfusions, including infections, hemolytic reactions, allergic reactions, transfusion-related lung injury (TRALI), transfusion-associated circulatory overload, and electrolyte imbalance.[rx][rx][rx]

According to the American Association of Blood Banks (AABB), febrile reactions are the most common, followed by transfusion-associated circulatory overload, allergic reaction, TRALI, hepatitis C viral infection, hepatitis B viral infection, human immunodeficiency virus (HIV) infection, and fatal hemolysis which is extremely rare, only occurring almost 1 in 2 million transfused units of RBC.

For comparison, the lifetime odds of dying from a lightning strike are about 1 in 161,000.

List of approximate risk per unit transfusion of RBC (adapted from AABB clinical guidelines published JAMA November 15, 2016).[rx]

Adverse Event and Approximate Risk Per Unit Transfusion of RBC

• Febrile reaction: 1:60
• Transfusion-associated circulatory overload: 1:100
• Allergic reaction: 1:250
• TRALI: 1:12,000
• Hepatitis C infection: 1:1,149,000
• Human immunodeficiency virus infection: 1:1,467,000
• Fatal hemolysis: 1:1,972,000

Febrile reactions are the most common transfusion adverse event. Transfusing with leukocyte-reduced blood products, which most blood products in the United States are, may help reduce febrile reactions. If this occurs, the transfusion should be halted, and the patient evaluated, as a hemolytic reaction can initially appear similar and consider performing a hemolytic or infectious workup. The treatment is with acetaminophen and, if needed, diphenhydramine for symptomatic control. After treatment and exclusion of other causes, the transfusion can be resumed at a slower rate.

Transfusion-associated circulatory overload is characterized by respiratory distress secondary to cardiogenic pulmonary edema. This reaction is most common in patients who are already in a fluid overloaded state, such as congestive heart failure or acute renal failure. Diagnosis is based on symptom onset within 6 to 12 hours of receiving a transfusion, clinical evidence of fluid overload, pulmonary edema, elevated brain natriuretic peptide, and response to diuretics.

Preventive efforts, as well as treatment, include limiting the number of transfusions to the lowest amount necessary, transfusing over the slowest possible time and administering diuretics before or between transfusions.

Allergic reaction, often manifested as urticaria and pruritis, occurs in less than 1% of transfusions. More severe symptoms, such as bronchospasm, wheezing, and anaphylaxis are rare. Allergic reactions may be seen in patients who are IgA deficient as exposure to IgA in donor products can cause a severe anaphylactoid reaction. This can be avoided by washing the plasma from the cells prior to transfusion. Mild symptoms, such as pruritis and urticaria can be treated with antihistamines. More severe symptoms can be treated with bronchodilators, steroids, and epinephrine.

Transfusion-related lung injury (TRALI) is uncommon, occurring in about 1:12,000 transfusion. Patients will develop symptoms within 2 to 4 hours after receiving a transfusion. Patients will develop acute hypoxemic respiratory distress, similar to acute respiratory distress syndrome (ARDS). Patients will have pulmonary edema without evidence of left heart failure, normal CVP. Diagnosis is made based on a history of recent transfusion, chest x-ray with diffuse patchy infiltrates, and the exclusion of other etiologies. While there is a 10% mortality, the remaining 90% will resolve within 96 hours with supportive care only.

Infections are a potential complication. The risk of infections has been decreased due to the screening of potential donors so that hepatitis C and human immunodeficiency virus risk are less than 1 in a million. Bacterial infection can also occur, but does so rarely, about once in every 250,000 units of red cells transfused.

Fatal hemolysis is extremely rare, occurring only in 1 out of nearly 2 million transfusions. It is the result of ABO incompatibility, and the recipient’s antibodies recognize and induce hemolysis in donor’s transfused cells. Patients will develop an acute onset of fevers and chills, low back pain, flushing, dyspnea as well as becoming tachycardic and going into shock. Treatment is to stop the transfusion, leave the IV in place, intravenous fluids with normal saline, keeping urine output greater than 100 mL/hour, diuretics may also be needed and cardiorespiratory support as appropriate. A hemolytic workup should also be performed which includes sending the donor blood and tubing as well as post-transfusion labs (see below for list) from the recipient to the blood bank.

• Retype and crossmatch
• Direct and indirect Coombs tests
• Complete blood count (CBC), creatinine, PT, and PTT (draw from the other arm)
• Peripheral smear
• Haptoglobin, indirect bilirubin, LDH, plasma free hemoglobin
• Urinalysis for hemoglobin

Electrolyte abnormalities can also occur, although these are rare, and more likely associated with large volume transfusion.

• Hypocalcemia can result as citrate, an anticoagulant in blood products binds with calcium.
• Hyperkalemia can occur from the release of potassium from cells during storage. Higher risk in neonates and patients with renal insufficiency.
• Hypokalemia can result as a result of alkalinization of the blood as citrate is converted to bicarbonate by the liver in patients with normal hepatic function.

References

Overview of Hemostasis

Hemostasis is the natural process that stops blood loss when an injury occurs.

Hemostasis is the natural process in which blood flow slows and clot forms to prevent blood loss during an injury, with hemo- meaning blood, and stasis meaning stopping. During hemostasis, blood changes from a fluid liquid to a gelatinous state.

Steps of Hemostasis

Hemostasis includes three steps that occur in a rapid sequence: (1) vascular spasm, or vasoconstriction, a brief and intense contraction of blood vessels; (2) formation of a platelet plug; and (3) blood clotting or coagulation, which reinforces the platelet plug with fibrin mesh that acts as a glue to hold the clot together. Once blood flow has ceased, tissue repair can begin.

Vasoconstriction

Intact blood vessels are central to moderating blood’s clotting tendency. The endothelial cells of intact vessels prevent clotting by expressing a fibrinolytic heparin molecule and thrombomodulin, which prevents platelet aggregation and stops the coagulation cascade with nitric oxide and prostacyclin. When the endothelial injury occurs, the endothelial cells stop the secretion of coagulation and aggregation inhibitors and instead secrete von Willebrand factor, which causes platelet adherence during the initial formation of a clot. The vasoconstriction that occurs during hemostasis is a brief reflexive contraction that causes a decrease in blood flow to the area.

Platelet Plug Formation

Platelets create the “platelet plug” that forms almost directly after a blood vessel has been ruptured. Within twenty seconds of an injury in which the blood vessel’s epithelial wall is disrupted, coagulation is initiated. It takes approximately sixty seconds until the first fibrin strands begin to intersperse among the wound. After several minutes, the platelet plug is completely formed by fibrin.

Contrary to popular belief, clotting of a skin injury is not caused by exposure to air, but by platelets adhering to and being activated by collagen in the blood vessels’ endothelium. The activated platelets then release the contents of their granules, which contain a variety of substances that stimulate further platelet activation and enhance the hemostatic process.

When the lining of a blood vessel breaks and endothelial cells are damaged, revealing subendothelial collagen proteins from the extracellular matrix, thromboxane causes platelets to swell, grow filaments, and start clumping together, or aggregating. Von Willebrand’s factor causes them to adhere to each other and the walls of the vessel. This continues as more platelets congregate and undergo these same transformations. This process results in a platelet plug that seals the injured area. If the injury is small, the platelet plug may be able to form within several seconds.

Coagulation Cascade

If the platelet plug is not enough to stop the bleeding, the third stage of hemostasis begins the formation of a blood clot. Platelets contain secretory granules. When they stick to the proteins in the vessel walls, they degranulate, thus releasing their products, which include ADP (adenosine diphosphate), serotonin, and thromboxane A2 (which activates other platelets).

First, blood changes from a liquid to a gel. At least 12 substances called clotting factors or tissue factors take part in a cascade of chemical reactions that eventually create a mesh of fibrin within the blood. Each of the clotting factors has a very specific function. Prothrombin, thrombin, and fibrinogen are the main factors involved in the outcome of the coagulation cascade. Prothrombin and fibrinogen are proteins that are produced and deposited in the blood by the liver.

When blood vessels are damaged, vessels and nearby platelets are stimulated to release a substance called prothrombin activator, which in turn activates the conversion of prothrombin, a plasma protein, into an enzyme called thrombin. This reaction requires calcium ions. Thrombin facilitates the conversion of a soluble plasma protein called fibrinogen into long, insoluble fibers or threads of the protein, fibrin. Fibrin threads wind around the platelet plug at the damaged area of the blood vessel, forming an interlocking network of fibers and a framework for the clot. This net of fibers traps and helps hold platelets, blood cells, and other molecules tight to the site of injury, functioning as the initial clot. This temporary fibrin clot can form in less than a minute and slows blood flow before platelets attach.

Next, platelets in the clot begin to shrink, tightening the clot and drawing together the vessel walls to initiate the process of wound healing. Usually, the whole process of clot formation and tightening takes less than a half hour.

Vascular Spasm

Vasoconstriction is the narrowing of the blood vessels, which reduces blood loss during injury.

Vasoconstriction is the narrowing of the blood vessels resulting from the contraction of the smooth muscle wall of the vessels, particularly in the large arteries and small arterioles. The process is the opposite of vasodilation, the dilation, and the expansion of blood vessels. During hemostasis, a brief spasm of vasoconstriction occurs, which slows blood flow into the injured area while the clot forms.

Mechanisms of Vasoconstriction

The vasoconstriction response is triggered by factors such as a direct injury to vascular smooth muscle, signaling molecules released by injured endothelial cells and activated platelets (such as thromboxane A₂), and nervous system reflexes initiated by local pain receptors. The spasm response becomes more effective as the amount of damage is increased. Vascular spasm is much more effective at slowing the flow of blood in smaller blood vessels. Vasoconstriction also causes an increase in blood pressure for affected blood vessels.

Smooth muscle in the vessel wall goes through intense contractions that constrict the vessel. If the vessels are small, spasms compress the inner walls together and may be able to stop the bleeding completely. If the vessels are medium to large-sized, the spasms slow down the immediate outflow of blood, lessening the damage but still preparing the vessel for the later steps of hemostasis. The spasm response becomes stronger and lasts longer in more severe injuries. Vasoconstriction may be induced by drugs called vasopressins, which increase blood pressure and can help treat certain conditions.

Injury and Inflammation

During injury, vasoconstriction is brief, lasting only a few minutes while the platelet plug and coagulation cascade occur. This is because as tissues are damaged during an injury, inflammation occurs as a result of inflammatory mediator release from immune system cells (such as mast cells or NK cells) that receive cell stress cytokines from damaged endothelial cells or vasoactive amines (serotonin) that are secreted by activated platelets. During inflammation, vasodilation occur, along with increased vascular permeability and leukocyte chemotaxis, ending the spasm of vasoconstriction and hemostasis as wound healing begins.

Platelet Plug Formation

At the site of vessel injury, platelets stick together to create a plug, which is the beginning of blood clot formation.

The second critical step in hemostasis, which follows vasoconstriction, is platelet plug formation. The three steps to platelet plug formation are platelet adherence, activation, and aggregation.

Platelet Adherence

Platelets: A blood slide of platelets aggregating or clumping together. The platelets are small, bright purple fragments.

The other factors released during platelet activation perform other important functions. Thromboxane is an arachidonic acid derivative (similar to prostaglandins) that activates other platelets and maintains vasoconstriction. Serotonin is a short-lived inflammatory mediator with a vasoconstrictive effect that contributes to vascular changes associated with inflammation during an injury. PDGF and VEGF are involved in angiogenesis, the growth of new blood vessels, and cell cycle proliferation (division) following injury. The coagulation factors include factors V and VIII, which are involved in the coagulation cascade that converts fibrinogen into fibrin mesh after platelet plug formation.

Platelet Aggregation

The final step of platelet plug formation is an aggregation of the platelets into a barrier-like plug. Receptors on the platelet bind to VWF and fibrinogen molecules, which hold the platelets together. Platelets may also bind to subendothelial VWF to anchor them to the damaged endothelium. The completed plug will cover the damaged components of the endothelium and will stop blood from flowing out of it, but if the wound is large enough, blood will not coagulate until the fibrin mesh from the coagulation cascade is produced, which strengthens the platelet plug. If the wound is minor, the platelet plug may be enough to stop the bleeding without the coagulation cascade.

Coagulation

Coagulation is the process by which a blood clot forms to reduce blood loss after damage to a blood vessel.

Coagulation is the process by which a blood clot forms to reduce blood loss after damage to a blood vessel. Several components of the coagulation cascade, including both cellular (e.g. platelets) and protein (e.g. fibrin) components, are involved in blood vessel repair. The role of the cellular and protein components can be categorized as primary hemostasis (the platelet plug) and secondary hemostasis (the coagulation cascade). The coagulation cascade is classically divided into three pathways: the contact (also known as the intrinsic) pathway, the tissue factor (also known as the extrinsic pathway), and the common pathway. Both the contact pathway and the tissue factor feed into and activate the common pathway.

Intrinsic Pathway

The intrinsic pathway (contact activation pathway) occurs during exposure to negatively charged molecules, such as molecules on bacteria and various types of lipids. It begins with formation of the primary complex on collagen by high-molecular-weight kininogen (HMWK), prekallikrein, and factor XII (Hageman factor). This initiates a cascade in which factor XII is activated, which then activates factor XI, which activated factor IX, which along with factor VIII activates factor X in the common pathway.

Extrinsic Pathway

The main role of the extrinsic (tissue factor) pathway is to generate a “thrombin burst,” a process by which large amounts of thrombin, the final component that cleaves fibrinogen into fibrin, is released instantly. The extrinsic pathway occurs during tissue damage when damaged cells release tissue factor III. Tissue factor III acts on tissue factor VII in circulation and feeds into the final step of the common pathway, in which factor X causes thrombin to be created from prothrombin.

Common Pathway

In the final common pathway, prothrombin is converted to thrombin. When factor X is activated by either the intrinsic or extrinsic pathways, it activates prothrombin (also called factor II) and converts it into thrombin using factor V. Thrombin then  cleaves fibrinogen into fibrin, which forms the mesh that binds to and strengthens the platelet plug, finishing coagulation and thus hemostasis. It also activates more factor V, which later acts as an anticoagulant with inhibitor protein C, and factor XIII, which covalently bonds to fibrin to strengthen its attachment to the platelets.

Coagulation Problems

While the coagulation cascade is critical for hemostasis and wound healing, it can also cause problems. An embolism is any thrombosis (blood clot)  that breaks off without being dissolved and travels through the bloodstream to another site. If it obstructs an artery that supplies blood to a tissue or organ, it can cause ischemia and infarcation to those tissues, leading to a pulmonary embolism, stroke, or heart attack).

Coagulation can occur even without injury, as blood pooling from prolonged immobility can cause clotting factors to accumulate and activate a coagulation cascade independently. Additionally, endothelial damage caused by immune system factors like inflammation or hypersensitivity may also cause unnecessary thrombosis and embolism. For example, during severe bacterial infections (septic shock), inflammation-induced tissue damage and the negatively charged molecules of bacteria activate both pathways of the coagulation cascade and cause disseminated intravascular coagulation (DIC), in which many clots form and break off, leading to massive organ failure.

Anticoagulants

Many anticoagulants prevent unnecessary coagulation, and those that genetically lack the ability to produce these molecules will be more susceptible to coagulation. These mechanisms include:

• Protein C: a vitamin K-dependent serine protease enzyme that degrades Factor V and factor VIII.
• Antithrombin: a serine protease inhibitor that degrades thrombin, Factor IXa, Factor Xa, Factor XIa, and Factor XIIa.
• Tissue factor pathway inhibitor (TFPI): limits the action of tissue factor (TF) and the factors it produces.
• Plasmin: generated by proteolytic cleavage of plasminogen, a potent fibrinolytic that degrades fibrin and destroys clots.
• Prostacyclin (PGI2): released by the endothelium and inhibits platelet activation.
• Thrombomodulin: released by the endothelium and converts thrombin into an inactive form.

Role of Vitamin K

Vitamin K is an essential factor of the coagulation cascade.

Coagulation is a complex cascade that requires many different cofactors and molecules to occur. Vitamin K, calcium, and phospholipids are necessary cofactors for proper coagulation, and people deficient in these substances will be more susceptible to uncontrolled bleeding.

Vitamin K

Vitamin K is a fat-soluble vitamin necessary for the synthesis of coagulation factors involved in the coagulation cascade. Factors II, VII, IX, and X are all important for the intrinsic and common pathways of coagulation. Vitamin K also synthesizes Protein C, Protein S, and Protein Z, anticoagulant proteins that degrade specific coagulation factors, preventing excessive thrombosis following the initial coagulation cascade.

Vitamin K can be inhibited by the anticoagulant drug warfarin, which acts as an antagonist for vitamin K. Warfarin is used in medicine for those at high risk of thromboembolism to prevent coagulation cascade by reducing vitamin K dependent synthesis of coagulation factors. Warfarin’s effects can be overcome by ingesting more vitamin K to reactivate the coagulation factor synthesis pathway.

Vitamin K deficiency is associated with impaired coagulation function and excessive bleeding and hemorrhage (internal bleeding, often severe). This can be caused by poor diet, malabsorption in the intestines, or liver failure. Those with vitamin K deficiency produce alternative proteins that improperly bind with phospholipids, which also contributes to the lack of coagulant function.

Calcium and Phospholipids

Calcium and phospholipids (a platelet membrane constituent) are required cofactors for prothrombin activation enzyme complexes to function. This enzyme is called tenase, and converts prothrombin to thrombin. Calcium mediates the binding of the tenase enzyme complexes (via the terminal gamma-carboxy residues on FXa and FIXa) to the phospholipid surfaces expressed by platelets, which in turn activates prothrombin to produce thrombin, which then produces fibrin from fibrinogen. Calcium acts as a catalyst for this reaction, speeding up the rate of the reaction to occur within the time frame of the factors involved in the coagulation cascade. Calcium is also required to synthesize the anticoagulant Protein C (along with vitamin K).

Calcium deficiencies inhibit proper blood coagulation. This can be caused by a nutritional deficiency or acute problems in which calcium is allocated elsewhere in the blood. Phospholipid deficiency is also associated with thrombocytopenia (platelet deficiency) because the phospholipids involved with clotting come from platelets. Thrombocytopenia causes more severe issues with blood clotting as the platelet plug will not be able to form or activate the coagulation cascade.

Clot Retraction and Repair

Clot retraction is the shrinking of a blood clot facilitated by thrombolytic agents.

The blood clots produced in hemostasis are merely the first step in repair and healing that occur after injury. Following a clot, inflammation draws leukocytes to the injury site to eliminate any pathogens that may have entered the body during the initial injury. Then, over the course of the next 24 hours, the clot retracts as tissue healing begins.

Clot Retraction

As the healing process occurs following blood clot formation, the clot must be destroyed in order to prevent thromboembolic events, in which clots break off from the endothelium and cause ischemic damage elsewhere in the body. By reducing the size of and breaking down the clot, the disease process can be arrested or the complications reduced.

Clot retraction refers to a regression in the size of the blood clot over a number of days. During this process, the edges of the endothelium at the point of injury are slowly brought together again to repair the damage. Clot retraction is dependent on the release of multiple coagulation factors released at the end of the coagulation cascade, most notably factor XIIIa cross-links. These factors cause the fibrin mesh to contract by forming twists and knots that condense the size of the clot. Clot retraction generally occurs within 24 hours of initial clot formation and decreases the size of the clot by 90%. Following clot retraction, a separate process called fibrinolysis occurs which degrades the fibrin of the clot while macrophages consume the expended platelets, thus preventing possible thromboembolism.

Wound Healing

While the clot retracts, the wound begins to heal. The first step of wound healing is epithelial cell migration, which forms a scab before the clot retracts. This occurs due to the stimulus of platelet-derived growth factor (PDGF). After clot retraction, true repair begins as tissue proliferation starts and collagen from the extracellular matrix is deposited in the wound while granulation tissue forms. Then new blood vessels grow into the healing tissue in a process called angiogenesis, which is stimulated by vascular endothelial growth factor (VEGF). The wound itself contracts, reducing in size. After these steps occur, new epithelial cells grow to cover the wound. If the wound was severe or unevenly shaped, or if healing takes too long, scarring may occur from collagen deposition. Most scarring on the skin is benign, but scarring inside the tissues of organs such as the heart or the lungs can cause health problems.

Fibrinolysis

Fibrinolysis is a process of breaking down clots in order to prevent them from growing and becoming problematic.

Fibrinolysis is a process that removes clots following hemostasis and clot retraction, preventing uncontrolled thrombosis and embolism. There are two types of fibrinolysis: primary fibrinolysis and secondary fibrinolysis. Primary fibrinolysis is a normal body process, whereas secondary fibrinolysis is the breakdown of clots due to a medication, medical disorder, or other cause.

Mechanisms of Primary Fibrinolysis

Primary fibrinolysis normally occurs following clot retraction, in which the clot has already condensed considerably in size. The main enzyme in primary fibrinolysis is plasmin, a proteolytic enzyme that degrades fibrin mesh. Plasmin cleaves fibrin at various places, leading to the production of circulating fragments that are cleared by other proteases or by the kidneys and liver.

Plasmin is produced in an inactive form, plasminogen, in the liver. Plasminogen cannot cleave fibrin and circulates in the bloodstream. Instead, it is incorporated into the clot when it is formed and then activated into plasmin later. Plasminogen is activated to plasmin by tissue plasminogen activator (t-PA) and urokinase, an enzyme found in the urine.

Fibrinolysis: Blue arrows denote stimulation and red arrows inhibition.

T-PA is released into the blood very slowly by the damaged endothelium of the blood vessels. T-PA and urokinase are themselves inhibited by plasminogen activator inhibitor-1 and plasminogen activator inhibitor-2 (PAI-1 and PAI-2). In contrast, plasmin further stimulates plasmin generation by producing more active forms of both tissue plasminogen activator (tPA) and urokinase. Following fibrin degradation by plasmin, old activated platelets from the platelet plug are phagocytized and destroyed by macrophages.

Alpha 2-antiplasmin and alpha 2-macroglobulin inactivate plasmin. Plasmin activity is also reduced by thrombin -activatable fibrinolysis inhibitor (TAFI), which modifies fibrin to make it more resistant to the tPA-mediated plasminogen. Plasmin operates on a negative feedback process because it is reduced when the fibrin clot is fully degraded.

Mechanisms of Secondary Fibrinolysis

Secondary fibrinolysis generally refers to the treatment of pathological thromboembolism. If blood clots embolize to different parts of the body, they can cause tissue death by blocking off blood flow to those tissues. This is a common cause of heart attacks, pulmonary embolism, and strokes. Several medications exist to help treat and prevent these conditions.

Fibrinolytic drugs include synthesized tissue plasminogen activator and streptokinase, a bacterial enzyme that has degraded fibrin directly. Clots may also be prevented or kept from worsening through the use of blood thinners ( anticoagulants ). Aspirin has anticoagulant properties because it inhibits cyclo-oxygenase-dependent pathways of platelet activation, which can prevent clotting from worsening. Heparin is a fast-acting anticoagulant produced by the body and used as a drug that inhibits the activity of thrombin. Warfarin inhibits vitamin K cofactor activation during the coagulation cascade, and citrates chelate calcium to prevent prothrombin activation into thrombin.

All of these treatments have been shown to have tremendous therapeutic benefits in treating those with thromboembolic diseases; however, they can make the injury much more difficult to treat by disrupting the clotting process. For example, patients thought to be suffering from a stroke (obstructed artery in the brain ) must be screened through imaging before given aspirin or a fibrinolytic drug, because if they have an aneurysm or hemorrhage (burst blood vessel or bleeding in the brain), administering fibrinolytic treatment would make their condition worse and possibly fatal by inhibiting the clotting that could save their lives.

References

Platelets Overviews

Platelets, also called thrombocytes, are membrane-bound cell fragments that are essential for clot formation during wound healing.

Platelets, also called thrombocytes, are membrane-bound cell fragments derived from the fragmentation of larger precursor cells called megakaryocytes, which are derived from stem cells in the bone marrow. Platelets are important for the blood clotting process, making them essential for wound healing.

Platelet Structure and Distribution

Platelets are irregularly shaped, have no nucleus, and typically measure only 2–3 micrometers in diameter. Platelets are not true cells but are instead classified as cell fragments produced by megakaryocytes. Because they lack a nucleus, they do not contain nuclear DNA. However, they do contain mitochondria and mitochondrial DNA, as well as endoplasmic reticulum fragments and granules from the megakaryocyte parent cells. Platelets also contain adhesive proteins that allow them to adhere to fibrin mesh and the vascular endothelium, as well as to a microtubule and microfilament skeleton that extends into filaments during platelet activation. Less than 1% of whole blood consists of platelets. They are about 1/10^th to 1/20^th as abundant as white blood cells.

Functions of Platelets

Platelets circulate in blood plasma and are primarily involved in hemostasis (stopping the flow of blood during injury), by causing the formation of blood clots, also known as coagulation. The adhesive surface proteins of platelets allow them to accumulate on the fibrin mesh at an injury site to form a platelet plug that clots the blood. The complex process of wound repair can only begin once the clot has stopped bleeding.

Platelets secrete many factors involved in coagulation and wound healing. During coagulation, they release factors that increase local platelet aggregation (thromboxane A), mediate inflammation (serotonin), and promote blood coagulation through increasing thrombin and fibrin (thromboplastin). They also release wound healing-associated growth factors including platelet-derived growth factor (PDGF), which directs cell movement; TGF beta, which stimulates the deposition of extracellular matrix tissue into a wound during healing; and vascular endothelial growth factor (VEGF), which stimulates angiogenesis, or the regrowth of blood vessels. These growth factors play a significant role in the repair and regeneration of connective tissues. Local application of these platelet-produced healing-associated factors in increased concentrations has been used as an adjunct to wound healing for several decades.

or

If the number of platelets is too low, excessive bleeding can occur and wound healing will be impaired. However, if the number of platelets is too high, blood clots can form (thrombosis), which may obstruct blood vessels and result in ischemic tissue damage caused by a stroke, myocardial infarction, pulmonary embolism, or the blockage of blood vessels to other parts of the body. Thrombosis also occurs when blood is allowed to pool, which causes clotting factors and platelets to form a blood clot even in the absence of an injury.

Platelet Formation

Platelets are membrane-bound cell fragments derived from megakaryocytes, which are produced during thrombopoiesis.

Platelets are small, clear, irregularly-shaped cell fragments produced by larger precursor cells called megakaryocytes. Platelets are also called thrombocytes because they are involved in the blood clotting process, which is necessary for wound healing. Platelets are continuously produced as a component product of hematopoiesis (blood cell formation).

Thrombopoiesis

Platelets are produced during hematopoiesis in a sub-process called thrombopoiesis, or the production of thrombocytes. Thrombopoiesis occurs from common myeloid progenitor cells in the bone marrow, which differentiate into promegakaryocytes and then into megakaryocytes. Megakaryocytes stay in the bone marrow and are thought to produce protoplatelets within their cytoplasm, which are released in cytoplasmic extensions upon cytokine stimulus. The protoplatelets then break up into hundreds of platelets that circulate throughout the bloodstream, while the remaining nucleus of the ruptured megakaryocyte is consumed by macrophages.

Megakaryocyte and platelet production is regulated by thrombopoietin, a hormone produced by the liver and kidneys. Thrombopoietin stimulates the differentiation of myeloid progenitor cells into megakaryocytes and causes the release of platelets. Thrombopoietin is regulated by a negative feedback mechanism based on platelet levels in the body so that high levels of platelets result in lower levels of thrombopoietin, while low levels of platelets result in higher levels of
thrombopoietin.

Each megakaryocyte produces between 5,000 and 10,000 platelets before its cellular components are fully depleted. Altogether, around 10^11 platelets are produced each day in a healthy adult. The average lifespan of a platelet is just 5 to 10 days. Old platelets are destroyed by macrophage phagocytosis in the spleen and by Kupffer cells in the liver. Up to 40% of platelets are stored in the spleen as a reserve, released when needed by sympathetically-induced splenic muscle contractions during severe injury.

Implications of Platelet Formation

Balanced thrombopoiesis is important because it directly influences the amount of platelets in the body and their associated complications. If the number of platelets is too low, excessive bleeding can occur, even from minor or superficial injuries. If the number of platelets is too high, blood clots can form (thrombosis) and travel through the bloodstream, which may obstruct blood vessels and result in ischemic events. These include stroke, myocardial infarction, pulmonary embolism, or infarction of other tissues.

An abnormality or disease of the platelets is called a thrombocytopathy, which could be either a low number of platelets (thrombocytopenia), a decrease in function of platelets (thrombasthenia), or an increase in the number of platelets (thrombocytosis). In any case, issues with the number of circulating platelets is often due to issues in thrombopoietin feedback regulation, but may also be associated with genetic characteristics and certain medications and diseases. For example, thrombocytopenia often occurs in leukemia patients. Cancerous myeloid cells crowd out healthy ones in the bone marrow, causing impaired thrombopoiesis.

Disorders of Platelets

The three broad categories of platelet disorders are “not enough”; “dysfunctional”; and “too many”.^[rx]:vii

Thrombocytopenia

• Immune thrombocytopenias (ITP) – formerly known as immune thrombocytopenic purpura and idiopathic thrombocytopenic purpura
• Splenomegaly
  • Gaucher’s disease
• Familial thrombocytopenia^[rx]
• Chemotherapy
• Babesiosis
• Dengue fever
• Onyalai
• Thrombotic thrombocytopenic purpura
• HELLP syndrome
• Hemolytic–uremic syndrome
• Drug-induced thrombocytopenic purpura (five known drugs – most problematic is heparin-induced thrombocytopenia (HIT)
• Pregnancy-associated
• Neonatal alloimmune associated
• Aplastic anemia
• Transfusion-associated
• Pseudothrombocytopenia
• idiopathic thrombocytopenic purpura
• Gilbert’s syndrome^[rx]

Altered platelet function

• Congenital
  • Disorders of adhesion
    • Bernard–Soulier syndrome
  • Disorders of activation
    • Disorders of granule amount or release
    • Hermansky–Pudlak syndrome
    • Gray platelet syndrome
    • ADP receptor defect
    • Decreased cyclooxygenase activity
    • Storage pool defects, acquired or congenital
  • Disorders of aggregation
    • Glanzmann’s thrombasthenia
    • Wiskott–Aldrich syndrome
• Acquired
  • Disorders of adhesion
    • Paroxysmal nocturnal hemoglobinuria
    • Asthma
    • Samter’s triad (aspirin-exacerbated respiratory disease/AERD)^[58]
    • Cancer
    • Malaria
    • Decreased cyclooxygenase activity

Thrombocytosis and thrombocythemia

• Reactive
  • Chronic infection
  • Chronic inflammation
  • Malignancy
  • Hyposplenism (post-splenectomy)
  • Iron deficiency
  • Acute blood loss
• Myeloproliferative neoplasms – platelets are both elevated and activated
  • Essential thrombocytosis
  • Polycythemia vera
• Associated with other myeloid neoplasms
• Congenital

What Causes Low Platelets?

References

Platelets Overviews

Platelets, also called thrombocytes, are membrane-bound cell fragments that are essential for clot formation during wound healing.

Platelets, also called thrombocytes, are membrane-bound cell fragments derived from the fragmentation of larger precursor cells called megakaryocytes, which are derived from stem cells in the bone marrow. Platelets are important for the blood clotting process, making them essential for wound healing.

Platelet Structure and Distribution

Platelets are irregularly shaped, have no nucleus, and typically measure only 2–3 micrometers in diameter. Platelets are not true cells but are instead classified as cell fragments produced by megakaryocytes. Because they lack a nucleus, they do not contain nuclear DNA. However, they do contain mitochondria and mitochondrial DNA, as well as endoplasmic reticulum fragments and granules from the megakaryocyte parent cells. Platelets also contain adhesive proteins that allow them to adhere to fibrin mesh and the vascular endothelium, as well as to a microtubule and microfilament skeleton that extends into filaments during platelet activation. Less than 1% of whole blood consists of platelets. They are about 1/10^th to 1/20^th as abundant as white blood cells.

Functions of Platelets

Platelets circulate in blood plasma and are primarily involved in hemostasis (stopping the flow of blood during injury), by causing the formation of blood clots, also known as coagulation. The adhesive surface proteins of platelets allow them to accumulate on the fibrin mesh at an injury site to form a platelet plug that clots the blood. The complex process of wound repair can only begin once the clot has stopped bleeding.

Platelets secrete many factors involved in coagulation and wound healing. During coagulation, they release factors that increase local platelet aggregation (thromboxane A), mediate inflammation (serotonin), and promote blood coagulation through increasing thrombin and fibrin (thromboplastin). They also release wound healing-associated growth factors including platelet-derived growth factor (PDGF), which directs cell movement; TGF beta, which stimulates the deposition of extracellular matrix tissue into a wound during healing; and vascular endothelial growth factor (VEGF), which stimulates angiogenesis, or the regrowth of blood vessels. These growth factors play a significant role in the repair and regeneration of connective tissues. Local application of these platelet-produced healing-associated factors in increased concentrations has been used as an adjunct to wound healing for several decades.

or

If the number of platelets is too low, excessive bleeding can occur and wound healing will be impaired. However, if the number of platelets is too high, blood clots can form (thrombosis), which may obstruct blood vessels and result in ischemic tissue damage caused by a stroke, myocardial infarction, pulmonary embolism, or the blockage of blood vessels to other parts of the body. Thrombosis also occurs when blood is allowed to pool, which causes clotting factors and platelets to form a blood clot even in the absence of an injury.

Platelet Formation

Platelets are membrane-bound cell fragments derived from megakaryocytes, which are produced during thrombopoiesis.

Platelets are small, clear, irregularly-shaped cell fragments produced by larger precursor cells called megakaryocytes. Platelets are also called thrombocytes because they are involved in the blood clotting process, which is necessary for wound healing. Platelets are continuously produced as a component product of hematopoiesis (blood cell formation).

Thrombopoiesis

Platelets are produced during hematopoiesis in a sub-process called thrombopoiesis, or the production of thrombocytes. Thrombopoiesis occurs from common myeloid progenitor cells in the bone marrow, which differentiate into promegakaryocytes and then into megakaryocytes. Megakaryocytes stay in the bone marrow and are thought to produce protoplatelets within their cytoplasm, which are released in cytoplasmic extensions upon cytokine stimulus. The protoplatelets then break up into hundreds of platelets that circulate throughout the bloodstream, while the remaining nucleus of the ruptured megakaryocyte is consumed by macrophages.

Megakaryocyte and platelet production is regulated by thrombopoietin, a hormone produced by the liver and kidneys. Thrombopoietin stimulates the differentiation of myeloid progenitor cells into megakaryocytes and causes the release of platelets. Thrombopoietin is regulated by a negative feedback mechanism based on platelet levels in the body so that high levels of platelets result in lower levels of thrombopoietin, while low levels of platelets result in higher levels of
thrombopoietin.

Each megakaryocyte produces between 5,000 and 10,000 platelets before its cellular components are fully depleted. Altogether, around 10^11 platelets are produced each day in a healthy adult. The average lifespan of a platelet is just 5 to 10 days. Old platelets are destroyed by macrophage phagocytosis in the spleen and by Kupffer cells in the liver. Up to 40% of platelets are stored in the spleen as a reserve, released when needed by sympathetically-induced splenic muscle contractions during severe injury.

Implications of Platelet Formation

Balanced thrombopoiesis is important because it directly influences the amount of platelets in the body and their associated complications. If the number of platelets is too low, excessive bleeding can occur, even from minor or superficial injuries. If the number of platelets is too high, blood clots can form (thrombosis) and travel through the bloodstream, which may obstruct blood vessels and result in ischemic events. These include stroke, myocardial infarction, pulmonary embolism, or infarction of other tissues.

An abnormality or disease of the platelets is called a thrombocytopathy, which could be either a low number of platelets (thrombocytopenia), a decrease in function of platelets (thrombasthenia), or an increase in the number of platelets (thrombocytosis). In any case, issues with the number of circulating platelets is often due to issues in thrombopoietin feedback regulation, but may also be associated with genetic characteristics and certain medications and diseases. For example, thrombocytopenia often occurs in leukemia patients. Cancerous myeloid cells crowd out healthy ones in the bone marrow, causing impaired thrombopoiesis.

Disorders of Platelets

The three broad categories of platelet disorders are “not enough”; “dysfunctional”; and “too many”.^[rx]:vii

Thrombocytopenia

• Immune thrombocytopenias (ITP) – formerly known as immune thrombocytopenic purpura and idiopathic thrombocytopenic purpura
• Splenomegaly
  • Gaucher’s disease
• Familial thrombocytopenia^[rx]
• Chemotherapy
• Babesiosis
• Dengue fever
• Onyalai
• Thrombotic thrombocytopenic purpura
• HELLP syndrome
• Hemolytic–uremic syndrome
• Drug-induced thrombocytopenic purpura (five known drugs – most problematic is heparin-induced thrombocytopenia (HIT)
• Pregnancy-associated
• Neonatal alloimmune associated
• Aplastic anemia
• Transfusion-associated
• Pseudothrombocytopenia
• idiopathic thrombocytopenic purpura
• Gilbert’s syndrome^[rx]

Altered platelet function

• Congenital
  • Disorders of adhesion
    • Bernard–Soulier syndrome
  • Disorders of activation
    • Disorders of granule amount or release
    • Hermansky–Pudlak syndrome
    • Gray platelet syndrome
    • ADP receptor defect
    • Decreased cyclooxygenase activity
    • Storage pool defects, acquired or congenital
  • Disorders of aggregation
    • Glanzmann’s thrombasthenia
    • Wiskott–Aldrich syndrome
• Acquired
  • Disorders of adhesion
    • Paroxysmal nocturnal hemoglobinuria
    • Asthma
    • Samter’s triad (aspirin-exacerbated respiratory disease/AERD)^[58]
    • Cancer
    • Malaria
    • Decreased cyclooxygenase activity

Thrombocytosis and thrombocythemia

• Reactive
  • Chronic infection
  • Chronic inflammation
  • Malignancy
  • Hyposplenism (post-splenectomy)
  • Iron deficiency
  • Acute blood loss
• Myeloproliferative neoplasms – platelets are both elevated and activated
  • Essential thrombocytosis
  • Polycythemia vera
• Associated with other myeloid neoplasms
• Congenital

What Causes Low Platelets?

References

Types of WBCs

The different types of white blood cells (leukocytes) include neutrophils, basophils, eosinophils, lymphocytes, monocytes, and macrophages.

White blood cells are much less common than red blood cells. There are five types of white blood cell (leucocyte). These are divided into two main classes

• Granulocytes (includes Neutrophils, Eosinophils and Basophils)
• Agranulocytes (includes Lymphocytes and Monocytes).

White blood cells (WBCs), or leukocytes, are immune system cells that defend the body against infectious disease and foreign materials. There are several different types of WBCs. They share commonalities but are distinct in form and function. WBCs are produced in the bone marrow by hemopoietic stem cells, which differentiate into either lymphoid or myeloid progenitor cells. A major distinguishing feature is the presence of granules; white blood cells are often characterized as granulocytes or agranulocytes.

Structure

Leukocytes can be classified as granulocytes and agranulocytes based on the presence and absence of microscopic granules in their cytoplasm when stained with Giemsa or Leishman stains.

Granulocytes 

Neutrophils, basophils, and eosinophils are all granulocytes. These cells also all have azurophilic granules (lysosomes) and specific granules that contain substances unique to each cell’s function. Histologically, granulocytes can be distinguished from one another by the morphology of their nucleus, their size, and how their granules stain.[1]

Neutrophils are 12 to 15 µm in diameter, have multi-lobed nuclei typically consisting of 3 to 5 segments joined by thin strands, or isthmuses. Thus, they are also called polymorphonuclear neutrophils. Neutrophils contain specific granules in the cytoplasm that cannot be resolved by light microscopy and therefore give the cytoplasm a pale pink color. Neutrophils, when activated, migrate into the tissues via diapedesis. These cells have life spans of a few days, and when activated in connective tissue, undergo apoptosis and are then removed by macrophages.

Eosinophils have a bi-lobed nucleus with large cytoplasmic specific granules that are eosinophilic, staining red to pink.

Basophils are 12 to15 µm in diameter, have bi-lobed or S-shaped nuclei, and contain cytoplasmic specific granules (0.5 µm) in diameter that stain blue to purple. The basophilia of the granules is due to the presence of heparin and sulfated glycosaminoglycans. These cells have similar functions as mast cells.

Agranulocytes

Agranulocytes consist of lymphocytes and monocytes, and while they lack specific granules, they do contain azurophilic granules.

Monocytes are precursor cells for the mononuclear phagocytic system, which include cells such as macrophages, osteoclasts, microglial cells in connective tissue and organs. These cells constitute 4 to 8% of white blood cells, are 12 to 15 µm in diameter, have large nuclei that are indented or C- shaped, which can be eccentric. There is abundant cytoplasm, and the lysosomal granules at the resolution of the light microscope give the cytoplasm bluish-gray color.

Lymphocytes constitute approximately 25% white blood cells, are of varying sizes, and have spherical nuclei. The small lymphocytes are similar in size to red blood cells, have spherical heterochromatic nuclei, and scant cytoplasm. Larger lymphocytes, such as activated lymphocytes, have indented nuclei and are 9 to 18 µm in diameter with more cytoplasm containing azurophilic granules. Lymphocytes subdivide into several groups using the cluster of differentiation (CD) markers. The major groups are B lymphocytes and T lymphocytes.

Granulocytes

Granulocytes, also known as polymorphonuclear (PMN) leukocytes, are characterized by stained granules within their cytoplasm under a microscope. These granules are membrane-bound enzymes that act primarily in the digestion of endocytosed particles. They may also cause granule-dependent cell-mediated apoptosis through the release of perforins, granzymes, and proteases. The nucleus contains multiple lobes (polymorphonuclear) as opposed to a single rounded lobe. Granulocytes contain toll-like receptors that allow them to recognize pathogen-associated molecular patterns (PAMPS). All categories except neutrophils contain IgE receptors that implicate them in allergic responses. There are four types of granulocytes:

• Neutrophils defend against bacterial or fungal infection and other very small inflammatory processes. They are usually the first responders to microbial infection. Their activity and death in large numbers from degranulation forms purulent necrosis (pus).
• Eosinophils primarily deal with parasitic infections. They are also the predominant inflammatory cells in allergic reactions.
• Basophils are chiefly responsible for short-term inflammatory response (particularly from allergy or irritation) by releasing the chemical histamine, which causes the vasodilation that occurs with inflammation.
• Mast cells function similarly to basophils in that they often mediate inflammation, but are more common and arise from a different hemopoietic lineage.

Mononuclear Leukocytes

Mononuclear (MN) leukocytes are characterized by a single round nucleus within the cytoplasm. Some MN leukocytes contain granules while others do not, but the members of this group are sometimes considered agranulocytes by naming convention. MN leukocytes contain lysosomes, small vesicles containing digestive enzymes that break down foreign matter that is endocytosed by the cell during phagocytosis. The cells include:

• Lymphocytes, which come in three types. B-lymphocytes produce antibodies in the humoral immune response. T-lymphocytes participate in the cell-mediated immune response. NK cells are cytotoxic cells that participate in the innate immune response by killing virally infected and tumor cells and mediating fever and long-lasting inflammation. B and T lymphocytes contain MHC antigen receptors and their activity is antigen-specific. Other leukocytes will attack any pathogen but cannot distinguish between different types of pathogens.
• Monocytes are large leukocytes that differentiate into macrophages and dendritic cells under varying conditions, while performing similar functions in phagocytosis and antigen presentation (the process by which molecular components are presented to lymphocytes to stimulate an adaptive immune response). Monocytes and their progeny contain toll-like receptors and granules.
• Macrophages are monocytes that have migrated out of the blood stream and into the internal body tissues. They destroy necrotic cell debris and foreign material including viruses and bacteria, and can present antigens to naive lymphocytes. They typically arrive at the site of inflammation one to three days after the initial neutrophil response to clean up dead neutrophils, cellular debris, and remaining pathogens.
• Dendritic cells are monocytes that have migrated to cells that are in contact with the external environment, such as the skin, intestines, or respiratory epithelium. Their name comes branched projections called dendrites, which increase their surface area. They phagocytize pathogens and present antigens to naive lymphocytes.

WBC Function

Each type of white blood cell (WBC) has a specific function in defending the body against infections.

Leukocytes ( white blood cells) provide a number of functions that are primarily related to defending the body from pathogens (foreign invaders). Much leukocyte activity takes place within the bloodstream but is not restricted to this area. Many leukocytes are able to perform their functions in tissues or organs during normal transport and in response to injury. Leukocyte functions may be classified as either innate or adaptive based on several characteristics.

Innate Immune System Functions

The innate immune system refers to the body’s ability to prevent pathogen entry and destroy pathogens that do enter the body. Its functions are rapid responses that inhibit a pathogen as soon as it is detected in the body. Innate immune system functions involving leukocytes include:

• Phagocytosis of pathogens. This process is performed primarily by neutrophils, macrophages, and dendritic cells, but most other leukocytes can do it as well. It involves the binding of an Fc receptor to a tail on a pathogen. The pathogen is engulfed by the leukocyte and destroyed with enzymes and free radicals.
• Inflammation. This process is performed primarily by mast cells, eosinophils, basophils, and NK cells. When a pathogen is detected or vascular endothelial cells release stress cytokines from injury such as a cut, leukocytes release a variety of inflammatory cytokines such as histamine or TNF-alpha. These cause vasodilation, increase vascular permeability, and promote neutrophil movement to the inflammation site.
• Degranulation. This process is performed by granulocytes like neutrophils. When pathogens are encountered, granule-dependent apoptosis (a mechanism of cytotoxicity) may be induced in the pathogen by releasing perforins, granzymes, and proteases from their granules.

Adaptive Immune System Functions

The adaptive immune system is specific to each pathogen on the basis of antigens, molecular components of pathogens used by leukocytes to recognize that specific pathogen. Compared to the innate immune system, adaptive immune functions work much faster and have a memory component that prevents reinfection by the same pathogen. However, more time typically passes before the adaptive immune system is functional. Adaptive immune functions of leukocytes include:

• Antigen presentation. This process is primarily performed by macrophages and dendritic cells. Following phagocytosis, protein components (antigens) of the pathogen are expressed on leukocyte MHC molecules and presented to naive T cells (and B cells) in the lymph nodes. The T cells will then start the adaptive immune response by rapidly proliferating and differentiating.
• Cell-mediated activities. This process is performed by T cells. Pathogens that bear the T cell’s antigen are destroyed through cytotoxic-induced apoptosis and protease activity.
• Humoral activities. This process is performed by B cells, which secrete antigen-specific antibodies. The antibodies bind to pathogens to opsonize (mark) them for phagocytes to engulf, neutralize, or start a complement cascade in which proteins form a membrane attack complex to lyse the pathogen.
• Memory cell activity. Following antigen presentation, memory B and T cells are created. These rapidly produce new T cells or antibodies if the same pathogen is detected in the future. This prevents that pathogen from reinfecting the organism.

WBC Formation

Hematopoiesis refers to the formation of blood cell components. It is necessary for vertebrate function.

Hematopoiesis refers to the formation of blood cellular components, including both white and red blood cells. All cellular blood components are derived from hematopoietic stem cells located within the bone marrow. In a healthy adult, approximately 10¹¹–10¹² new blood cells are produced daily to maintain equilibrium levels in the peripheral circulation.

Leukocyte Haematopoiesis

Hematopoietic stem cells (HSCs) reside in the bone marrow and have the unique ability to give rise to all mature blood cell types through differentiation into other progenitor cells. HSCs are self-renewing. When they proliferate, at least some daughter cells remain HSCs, so the pool of stem cells does not become depleted over time. The daughters are the myeloid and lymphoid progenitor cells, which cannot self renew but differentiate into various myeloid leukocytes and lymphocytes respectively. This is one of the body’s vital processes.

Leukocyte Lineages

Two different leukocyte lineages and two non-leukocyte lineages arise from the progeny of HSCs. Following this split in differentiation, the subtypes undergo eventual differentiation into terminally-differentiated leukocytes, which typically do not divide independently.

1. The lymphocyte lineage derives from common lymphoid progenitor cells, which in turn become lymphoblasts before differentiating into T cells, B cells, and NK cells.
2. Myelocytes are an offshoot of common myeloid progenitor cells, which also differentiate into the erythropoietic and magakaryotic progenitors. This diverse group differentiates into granulocytes and monocytes. Monocytes further differentiate into macrophages or dendritic cells upon reaching certain tissues.
3. Megakaryocytes (the cells that produce platelets) and erythrocytes (red blood cells) are not formally considered to be leukocytes, but arise from the common myeloid progenitor cells that produce the other cellular components of blood.

Sites of Hematopoiesis in Pre- and Postnatal Periods

In developing embryos, blood formation occurs in aggregates of blood cells in the yolk sac called blood islands. However, most of the blood supply comes from the mother through the placenta. As development progresses, blood formation occurs primarily in the spleen, liver, and lymph nodes.

When bone marrow develops, it eventually assumes the task of forming most of the blood cells for the entire organism. However, maturation, activation, and some proliferation of lymphoid cells occur in lymphoid organs (spleen, thymus, and lymph nodes). In children, hematopoiesis occurs in the marrow of the long bones such as the femur and tibia. In adults, it occurs mainly in the pelvis, cranium, vertebrae, and sternum.

In some cases, the liver, thymus, and spleen may resume their hematopoietic function if necessary. This is called extramedullary hematopoiesis. It may cause these organs to hypertrophy and increase in size substantially. During fetal development, the liver functions as the main haematopoetic organ since bones and marrow develop later. Therefore, the liver is enlarged during development relative to its mature proportions.

Disorders

The two commonly used categories of white blood cell disorders divide them quantitatively into those causing excessive numbers (proliferative disorders) and those causing insufficient numbers (leukopenias).^[rx] Leukocytosis is usually healthy (e.g., fighting an infection), but it also may be dysfunctionally proliferative. WBC proliferative disorders can be classed as myeloproliferative and lymphoproliferative. Some are autoimmune, but many are neoplastic.

Another way to categorize disorders of white blood cells is qualitative. There are various disorders in which the number of white blood cells is normal but the cells do not function normally.^[rx]

Neoplasia of WBCs can be benign but is often malignant. Of the various tumors of the blood and lymph, cancers of WBCs can be broadly classified as leukemias and lymphomas, although those categories overlap and are often grouped as a pair.

Leucopenias

A range of disorders can cause decreases in white blood cells. This type of white blood cell decreased is usually the neutrophil. In this case the decrease may be called neutropenia or granulocytopenia. Less commonly, a decrease in lymphocytes (called lymphocytopenia or lymphopenia) may be seen.^[rx]

Neutropenia

Neutropenia can be acquired or intrinsic.^[rx] A decrease in levels of neutrophils on lab tests is due to either decreased production of neutrophils or increased removal from the blood.^[rx] The following list of causes is not complete.

• Medications – chemotherapy, sulfates or other antibiotics, phenothiazines, benzodiazepines, antithyroid, anticonvulsants, quinine, quinidine, indomethacin, procainamide, thiazides
• Radiation
• Toxins – alcohol, benzenes
• Intrinsic disorders – Fanconi’s, Kostmann’s, cyclic neutropenia, Chédiak–Higashi
• Immune dysfunction – disorders of collagen, AIDS, rheumatoid arthritis
• Blood cell dysfunction – megaloblastic anemia, myelodysplasia, marrow failure, marrow replacement, acute leukemia
• Any major infection
• Miscellaneous – starvation, hypersplenism

Symptoms of neutropenia are associated with the underlying cause of the decrease in neutrophils. For example, the most common cause of acquired neutropenia is drug-induced, so an individual may have symptoms of medication overdose or toxicity. Treatment is also aimed at the underlying cause of neutropenia.^[rx] One severe consequence of neutropenia is that it can increase the risk of infection.^[rx]

Lymphocytopenia

Defined as total lymphocyte count below 1.0×10⁹/L, the cells most commonly affected are CD4+ T cells. Like neutropenia, lymphocytopenia may be acquired or intrinsic and there are many causes.^[rx] This is not a complete list.

• Inherited immune deficiency – severe combined immunodeficiency, common variable immune deficiency, ataxia-telangiectasia, Wiskott–Aldrich syndrome, immunodeficiency with short-limbed dwarfism, immunodeficiency with thymoma, purine nucleoside phosphorylase deficiency, genetic polymorphism
• Blood cell dysfunction – aplastic anemia
• Infectious diseases – viral (AIDS, SARS, West Nile encephalitis, hepatitis, herpes, measles, others), bacterial (TB, typhoid, pneumonia, rickettsiosis, ehrlichiosis, sepsis), parasitic (acute phase of malaria)
• Medications – chemotherapy (antilymphocyte globulin therapy, alemtuzumab, glucocorticoids)
• Radiation
• Major surgery
• Miscellaneous – ECMO, kidney or bone marrow transplant, hemodialysis, kidney failure, severe burns, celiac disease, severe acute pancreatitis, sarcoidosis, protein-losing enteropathy, strenuous exercise, carcinoma
• Immune dysfunction – arthritis, systemic lupus erythematosus, Sjögren syndrome, myasthenia gravis, systemic vasculitis, Behcet-like syndrome, dermatomyositis, granulomatosis with polyangiitis
• Nutritional/Dietary – alcohol use disorder, zinc deficiency

Like neutropenia, symptoms and treatment of lymphocytopenia are directed at the underlying cause of the change in cell counts.

Proliferative disorders

An increase in the number of white blood cells in circulation is called leukocytosis.^[rx] This increase is most commonly caused by inflammation.^[rx] There are four major causes: increase of production in bone marrow, increased release from storage in bone marrow, decreased attachment to veins and arteries, decreased uptake by tissues.^[rx] Leukocytosis may affect one or more cell lines and can be neutrophilic, eosinophilic, basophilic, monocytosis, or lymphocytosis.

Neutrophilia

Neutrophilia is an increase in the absolute neutrophil count in the peripheral circulation. Normal blood values vary by age.^[rx] Neutrophilia can be caused by a direct problem with blood cells (primary disease). It can also occur as a consequence of an underlying disease (secondary). Most cases of neutrophilia are secondary to inflammation.^[rx]

Primary causes^[rx]

• Conditions with normally functioning neutrophils – hereditary neutrophilia, chronic idiopathic neutrophilia
• Pelger–Huët anomaly
• Down syndrome
• Leukocyte adhesion deficiency
• Familial cold urticaria
• Leukemia (chronic myelogenous (CML)) and other myeloproliferative disorders
• Surgical removal of spleen^[rx]

Secondary causes^[rx]

• Infection
• Chronic inflammation – especially juvenile rheumatoid arthritis, rheumatoid arthritis, Still’s disease, Crohn’s disease, ulcerative colitis, granulomatous infections (for example, tuberculosis), and chronic hepatitis
• Cigarette smoking – occurs in 25–50% of chronic smokers and can last up to 5 years after quitting
• Stress – exercise, surgery, general stress
• Medication-induced – corticosteroids (for example, prednisone, β-agonists, lithium)
• Cancer – either by growth factors secreted by the tumor or invasion of bone marrow by the cancer
• Increased destruction of cells in peripheral circulation can stimulate bone marrow. This can occur in hemolytic anemia and idiopathic thrombocytopenic purpura

Eosinophilia

A normal eosinophil count is considered to be less than 0.65×10⁹/L.^[rx] Eosinophil counts are higher in newborns and vary with age, time (lower in the morning and higher at night), exercise, environment, and exposure to allergens.^[rx] Eosinophilia is never a normal lab finding. Efforts should always be made to discover the underlying cause, though the cause may not always be found.^[rx]

References

RBC Anatomy

Red blood cells lack nuclei and have a biconcave shape.

Human erythrocytes or red blood cells (RBCs) are the primary cellular component of blood. They are involved in oxygen transport through the body and have features that distinguish them from every other type of human cell. Adult humans have roughly 20-30 trillion RBCs at any given time, comprising approximately one-quarter of the total number of human cells.

External Structure

RBCs are disc-shaped with a flatter, concave center. This biconcave shape allows the cells to flow smoothly through the narrowest blood vessels. Gas exchange with tissues occurs in capillaries, tiny blood vessels that are only as wide as one cell. Many RBCs are wider than capillaries, but their shape provides the needed flexibility to squeeze through.

A typical human RBC has a disk diameter of 6–8 micrometers and a thickness of 2 micrometers, much smaller than most other human cells. These cells have an average volume of about 90 femtoliters (fL) with a surface area of about 136 square micrometers. They can swell up to a sphere shape containing 150 fL without bursting their cell membrane. When the shape does change, it inhibits their ability to carry oxygen or participate in gas exchange. This occurs in people with spherocytic (sphere-shaped) anemia or sickle-cell anemia.

Internal Structure

Although RBCs are considered cells, they lack a nucleus, nuclear DNA, and most organelles, including the endoplasmic reticulum and mitochondria. RBCs therefore cannot divide or replicate like other labile cells of the body. They also lack the components to express genes and synthesize proteins. While most cells have chemotaxis ways to travel through the body, RBCs are carried through the body by blood flow and pressure alone.

Hemoglobin molecules are the most important component of RBCs. Hemoglobin is a specialized protein that contains a binding site for the transport of oxygen and other molecules. The RBCs’ distinctive red color is due to the spectral properties of the binding of hemic iron ions in hemoglobin. Each human red blood cell contains approximately 270 million of these hemoglobin biomolecules, each carrying four heme groups (individual proteins). Hemoglobin comprises about a third of the total RBC volume. This protein is responsible for the transport of more than 98% of the oxygen, while the rest travels as dissolved molecules through the plasma.

RBC Physiology

The primary functions of red blood cells (RBCs) include carrying oxygen to all parts of the body, binding to hemoglobin, and removing carbon dioxide.

Red blood cells (RBCs) perform a number of human respiratory and cardiovascular system functions. Most of these functions are attributed to hemoglobin content. The main RBC functions are facilitating gas exchange and regulating blood pH.

Gas Exchange

Heme: This is a diagram of the molecular structure of heme.

The binding of oxygen is a cooperative process. Hemoglobin bound oxygen causes a gradual increase in oxygen-binding affinity until all binding sites on the hemoglobin molecule are filled. As a result, the oxygen-binding curve of hemoglobin (also called the oxygen saturation or dissociation curve) is sigmoidal, or S-shaped, as opposed to the normal hyperbolic curve associated with noncooperative binding. This curve shows the saturation of oxygen bound to hemoglobin compared to the partial pressure of oxygen (concentration) in blood.

pH Control

RBCs control blood pH by changing the form of carbon dioxide within the blood. Carbon dioxide is associated with blood acidity. That’s because most carbon dioxide travels through the blood as a bicarbonate ion, which is the dissociated form of carbonic acid in the solution. The respiratory system regulates blood pH by changing the rate at which carbon dioxide is exhaled from the body, which involves the RBC’s molecular activity. RBCs alter blood pH in a few different ways.

Quaternary structure: hemoglobin: Hemoglobin is a globular protein composed of four polypeptide subunits (two alpha chains, in blue, and two beta-pleated sheets, in red). The heme groups are the green structures nestled among the alpha and beta.

RBCs secrete the enzyme carbonic anhydrase, which catalyzes the conversion of carbon dioxide and water to carbonic acid. This dissociates in solution into bicarbonate and hydrogen ions, the driving force of pH in the blood. This reaction is reversible by the same enzyme. Carbonic anhydrase also removes water from carbonic acid to turn it back into carbon dioxide and water. This process is essential so carbon dioxide can exist as a gas during a gas exchange in the alveolar capillaries. As carbon dioxide is converted from its dissolved acid form and exhaled through the lungs, blood pH becomes less acidic. This reaction can occur without the presence of RBCs or carbonic anhydrase but at a much slower rate. With the catalyst activity of carbonic anhydrase, this reaction is one of the fastest in the human body.

Hemoglobin can also bind to carbon dioxide, which creates carbamino-hemoglobin. When carbon dioxide binds to hemoglobin, it doesn’t exist in the form of carbonic acid, which makes the blood less acidic and increases blood pH. However, because of allosteric effects on the hemoglobin molecule, the binding of carbon dioxide decreases the amount of oxygen bound for a given partial pressure of oxygen. This decrease in hemoglobin’s affinity for oxygen by the binding of carbon dioxide is known as the Bohr effect, which results in a rightward shift to the O₂-saturation curve. Conversely, when the carbon dioxide levels in the blood decrease (i.e., in the lung capillaries), carbon dioxide and hydrogen ions are released from hemoglobin, increasing the oxygen affinity of the protein. A reduction in the total binding capacity of hemoglobin to oxygen (i.e. shifting the curve down, not just to the right) due to reduced pH is called the Haldane effect.

RBC Life Cycle

Human erythrocytes are produced through a process called erythropoiesis. They take about seven days to mature.

Human erythrocytes are produced through a process called erythropoiesis, developing from committed stem cells to mature erythrocytes in about seven days. When matured, these cells circulate in the blood for about 100 to 120 days, performing their normal function of molecule transport. At the end of their lifespan, they degrade and are removed from circulation.

Erythropoiesis

Erythropoiesis is the process in which new erythrocytes are produced, which takes about seven days. Erythrocytes are continuously produced in the red bone marrow of large bones at a rate of about 2 million cells per second in a healthy adult. Erythrocytes differentiate from erythropoietic bone marrow cells, a type of hemopoietic stem cell found in the bone marrow. Unlike mature RBCs, bone marrow cells contain a nucleus. In the embryo, the liver is the main site of red blood cell production and bears similar types of stem cells at this stage of development.

Erythropoiesis can be stimulated by the hormone erythropoietin, which is synthesized by the kidney in response to hypoxia (systemic oxygen deficiency). In the last stages of development, immature RBCs absorb iron, Vitamin B12, and folic acid. These dietary nutrients are necessary for the proper synthesis of hemoglobin (iron) and normal RBC development (B12 and folic acid). Deficiency of any of these nutrients may cause anemia, a condition in which there aren’t enough fully functional RBCs carrying oxygen in the bloodstream. Just before and after leaving the bone marrow, the developing cells are known as reticulocytes. These immature RBCs have shed their nuclei following initial differentiation. After 24 hours in the bloodstream, reticulocytes mature into functional RBCs.

Eryptosis

Eryptosis, a form of apoptosis (programmed cell death), is the aging and death of mature RBCs. As an RBC age, it undergoes changes in its plasma membrane that make it susceptible to selective recognition by macrophages and subsequent phagocytosis in the reticuloendothelial system (spleen, liver, and bone marrow). This process removes old and defective cells and continually purges the blood. Eryptosis normally occurs at the same rate as erythropoiesis, keeping the total circulating red blood cell count in a state of equilibrium. Many diseases that involve damage to RBCs (hemolytic anemias, sepsis, malaria, pernicious or nutritional anemias) or normal cellular processes that cause cellular damage (oxidative stress) may increase the rate of eryptosis. Conversely, erythropoietin and nitric oxide (a vasodilator) will inhibit eryptosis.

Following eryptosis, the hemoglobin content within the RBC is broken down and recirculated throughout the body. The heme components of hemoglobin are broken down into iron ions and a green bile pigment called biliverdin. The biliverdin is reduced to the yellow bile pigment bilirubin, which is released into the plasma and recirculated to the liver, then bound to albumin and stored in the gallbladder. The bilirubin is excreted through the digestive system in the form of bile, while some of the iron is released into the plasma to be recirculated back into the bone marrow by a carrier protein called transferrin.  This iron is then reused for erythropoiesis, but additional dietary iron is needed to support healthy RBC life cycles.