Endo + Heme

Endocrine
Chemical substances secreted by cells into the extracellular fluids that travel through the blood and regulate the metabolic function of other cells in the body are called hormones. The primary function of hormones is to act as chemical messengers that regulate the metabolic function of cells in the body. The primary function of hormones is to affect cellular metabolism by altering plasma membrane permeability or membrane potential, stimulating synthesis of enzymes, activating or deactivating enzymes, including secretory activity, or stimulating mitosis.
Glands that secrete their products into surrounding tissues fluids are classified as endocrine glands, whereas glands that secrete into a membrane surface are classified as exocrine glands. The major glands of the endocrine system include the pineal gland, pituitary gland, pancreas, ovaries, testes, thyroid gland, parathyroid gland, hypothalamus, and adrenal glands.  Adenoids are the tonsils, aka part of the lymph system.
Amino acid-based hormones require a receptor in the plasma membrane. This is because they are water-soluble, hence not able to go through the phospholipid-bilayer membrane and have to stay outside. Steroid-based hormones are lipid-soluble and can go through the phospholipid-bilayer membrane, hence able to interact with receptors inside the cell and nucleus. Water-soluble hormones are inactivated and removed from the blood by the kidneys. Amino acid-based hormones will have the suffix -ine (ie. - norepinephrine, epinephrine, thyroxine, catecholamines, etc.). It looks like steroid-based hormones do not have any specific pattern.
A hormone typically produces one or more of the following changes: alters plasma membrane permeability or membrane potential, or both by opening of closing ion channels; stimulates synthesis of enzymes and other proteins within the cell; activates or deactivates enzymes; induces secretory activity; and/or stimulates mitosis.
Hormones signal through two major mechanisms: via second messengers or direct gene action. Since water-soluble hormones (most amino-acid based hormones) cannot enter the target cell directly, they act through plasma membrane receptors and intracellular second messengers. Lipase-soluble hormones (steroid and thyroid hormones) can diffuse through the plasma membrane and act on intracellular receptors in the target cells to directly activate genes. Some important examples of second messengers include cyclic AMP (cAMP), diacylglycerol (DAG), inositol triphosphate (IP3), and calcium ions (Ca2+). Second messengers are the second step following the release of the first messenger and they produce large, but slow target cells effects. The main benefit of second messenger systems is the amplification of the hormonal signal. A single hormone binding to a receptor on the cell surface can generate thousands of second messengers inside of the cell, which in turn can affect millions of protein, producing a huge cellular response. Given the numerous steps involved, these pathways sacrifice speed of response for magnitude of response.
Humoral stimuli, neural stimuli, and hormonal stimuli are the three types of stimulus that trigger endocrine glands to manufacture and release hormones.
Humoral stimuli are classified as any changing blood levels of ions/nutrients that would directly stimulate the secretion of the hormone. For example, a rise in blood glucose levels triggers the pancreatic release of insulin. The insulin causes the blood glucose levels to decrease, which signals the pancreas to stop producing insulin. This is a negative feedback loop. Parathyroid hormone production is an example of this as well, as is part of aldosterone production.
Neural stimuli are classified as the nerve fibers themselves stimulating hormone release. An example of this is when the body needs to respond to a flight-or-fight response. Neural signaling from the sympathetic nervous system directly stimulates the adrenal medulla to release the hormones epinephrine and norepinephrine in response to the stress.
Hormonal stimuli are classifies as hormones from one area stimulating the release of hormones from another organ. An example of this is that hypothalamic hormones stimulate the release of most anterior pituitary gland (APG) hormones, which then (the AP hormones) stimulate targets to secrete still more hormones, creating a positive feedback loop.  Testosterone production is an example of this as well, as is part of aldosterone production.
The presence of a specific hormone receptor is what determines whether a particular cell is able to respond to a hormone. Any cell that has a specific receptor for a specific hormone is a target cell of that hormone. Binding of the hormone to the receptor triggers a response from the target cell. Up-regulation involves the formation of more receptors in response to decreased hormone concentrations over a prolonged period of time. Prolonged exposure to high hormone concentrations would result in down-regular, which involves a decrease in the number of receptors for that hormone. Down-regulation desensitizes the target cells, so they respond less vigorously to hormonal stimulation, preventing them from overreacting to persistently high hormone levels.
cAMP signaling (second messengers in water-soluble hormones) works in the specific order: 1) Water-soluble hormones binds to the receptor (present through both sides of the membrane, changing structure of the receptor) , 2) Receptor activates the Gs-protein (Gs-protein present along the inner membrane surface, discards normally present GDP for free-floating GTP), 3) Gs-protein activates adenylate cyclase (otherwise inactive membrane protein), 4) The activated adenylate cyclase generates cAMP (cyclic AMP, by binding ATP that had been free-floating within the cell), and 5) cAMP activates the inactive protein kinases (present free-floating within the cell). The activated protein kinases phosphorylate many proteins within the cell (via activation of some and deactivation of others), thus changing their activity and then changing the cell’s response when exposed to the hormone. Deactivation of the cAMP begins once the hormone is no longer bound to the receptor. The GTP on the Gs-protein (still hooked up with the adenylate cyclase) is converted into GDP, thus deactivating the G-protein. At this point, G-protein and adenylate cyclase break apart and adenylate cyclase becomes inactive again, thus producing no more cAMP from the ATP. Existing free-floating cAMP present within the cell are degraded by the enzyme phosphodiesterase (free-floating within the cell as well) into AMP. Protein kinases then inactivate with the lack of cAMP, thus preventing further phosphorylation. We are now back to baseline at this point. Some important things to note is that the hormone is the first messenger and the cAMP is the second messenger. The initial receptors are determined by their ability to activate the Gs-protein or are involved with protein kinase activity. The phosphorylation activity of the protein kinases can include affecting ion channels in the membrane. G-proteins, like the ones we went through are stimulatory, but there are also inhibitory G-proteins that inhibit production of cAMP and the subsequent response of the cell. Another type of G-protein activates an intracellular messenger system that uses diacylglycerol and inositol triphosphate as second messengers. When a hormone binds to the receptor, the receptor changes shape and activates the G-protein, like normal. GDP is released from the G-protein and GTP is bound, like normal. The activated G-protein travels along the membrane to activate a membrane enzyme, phospholipase C. The activated phospholipase C then attaches to phosphatidylinositol bisphosphate (PIP2), membrane phospholipid, to cleave into diacylglycerol (DAG) and inositol triphosphate (IP3). Both of these act as second messengers: DAG remains in the membrane where it activates protein kinase C, while IP3 enters the cytosol. The activated protein kinase C phosphorylates other proteins causing responses of the cell, like normal. IP3 prompts the endoplasmic reticulum (ER) to release calcium ions (Ca2+) which then also behave like second messengers. Ca2+ can act directly on proteins or bind to the protein calmodulin that can act on proteins to cause the response of the cell. Another type of plasma membrane receptor utilizes protein kinase activity for its effect (ie- hormones that bind to tyrosine kinase receptors). When a hormone binds to the tyrosine kinase receptor (present across the membrane), the receptor connects to the neighboring tyrosine kinase receptor.  Once these have connected, the structures change shape, such that they are able to phosphorylate tyrosine groups for each other (autophosphorylation, but only when the receptors are of the same type). The phosphorylated tyrosine groups provide docking sites where relay proteins bind, which indicates a series of protein phosphorylation’s that lead to the response of the cell. Receptors with tyrosine kinase activity often bind hormones like insulin and other growth factors that affect cell growth and differentiation. It should be noted that β-receptors that bind epinephrine and norepinephrine (adrenergic receptors) increase cAMP levels.
The hypothalamus is connected to the PG via the stalk called the infundibulum. The hormones that the hypothalamus secretes are strictly regulating hormones that release or inhibit other hormones throughout the body. This is primarily TRH (that regulates the secretion of TSH, which happens to regulate the secretion of TH).
The APG is primarily composed of glandular tissue while the PPG is primarily composed of neural tissue. The PPG, along with the infundibulum, makes up the neurohypophysis.
Hormonal stimuli from the hypothalamus is what is directly required for the production of APG hormones. PRL is produced in the APG, where it is also stored. PRL stimulates the mammary glands of the nursing mother to produce milk. After birth, the infant suckling stimulates release of PRL-releasing factors in the mother, encouraging continued milk production. Hormones associated with the APG include growth hormone (GH/somatotropin) which affects bones and muscles, prolactin (PRL) which affects mammary glands, follicle stimulating hormone (FSH) and luteinizing hormone (LH) which affects testes/ovaries, thyroid-stimulating hormone (TSH) which affects the thyroid, and adrenocorticotropic hormone (ACTH/corticotropin) which affects the adrenal cortex. TSH, ACTH, FSH, and LH are tropic, meaning they affect other glands, while GH and PRL are not. In addition, all APG hormones, except GH, affect their target cells via a cAMP second-messenger system.
GH is produced by somatotropic cells in the APG and has direct actions of metabolism and indirect growth- actions. The direct actions include glucose-sparring actions (decreased the rate of cellular glucose uptake and metabolism aka an anti-insulin effect), triggering the liver to break down glycogen into glucose, and increasing blood levels of fatty acids for use as fuel and encourages cellular protein synthesis. Indirect actions include triggering the liver, skeletal muscle, and bone to produce insulin-like growth factors (IGF’s, which then stimulate cellular uptake of nutrients used to synthesize DNA and proteins needed for cell division, as well as forming collagen and deposing the bone matrix), and stimulates most cells to enlarge and divide (major targets are bone and skeletal muscle). GH is released and inhibited by hypothalamic hormones on somatotropic cells (GHRH releasing, released by low blood GH or glucose or high amino acids, and GHIH inhibiting, released by increase in GH and IGF levels). Too much gets you gigantism and too little gets you dwarfism.
TSH is produced by thyrotropic cells in the APG and stimulates normal development and secretory activity of the thyroid. TSH is released by thyrotropin-releasing hormones (TTRH), which had been produced in the hypothalamus. TSH is inhibited by rising blood levels of thyroid hormones that act on both the pituitary gland and the hypothalamus, as well as GHIH.
Hypothalamus  --TRH stimulates--> APG --TSH stimulates--> thyroid gland --thyroid hormones stimulates--> target cells
--thyroid hormones inhibits--> hypothalamus + APG
ACTH is secreted by corticotropic cells in the APG (precursor is proopiomelanocortin) and stimulates the adrenal cortex to release corticosteroids. These then retain sodium and water, increased blood sugar, and begin breaking down fats. ACTH release is regulated by the triggering of hypothalamic corticotropin-releasing hormones (CRH) in daily rhythms, as well as internal and external stressors (like short- and long-term stress and illness).
Stress --> CRH (hypothalamus) --> ACTH (APG) --> cortisol (ZF of the adrenal cortex) --> tissues
						Cortisol then responds by inhibiting CRH and ACTH
FSH is secreted by gonadotropic cells of the APG. FSH stimulates follicle development and estrogen production in the ovaries and sperm production in the testes. LH promotes productions of gonadal hormones. In females, LH helps mature follicles of eggs, triggers ovulation and the release of estrogen and progesterone. In males, LH stimulates production of testosterone. LH and FSH are absent from blood in prepubescent boys and girls. Gonadotropin release is regulated by gonadotropin-releasing hormone (GnRH) during and after puberty and is suppressed by gonadal hormones (aka feedback).
PRL is secreted by PRL cells in the APG. PRL stimulates milk production in females and essentially nothing in males. PRL is regulated by prolactin-inhibiting hormone (PIH aka dopamine). PIH prevents the release of PRL until PRL is needed, with decreased levels of PIH leading to lactation. Increased estrogen levels are known to stimulate PRL, as evidenced by breast swelling and tenderness during the menstrual cycle. PRL blood levels are known to rise towards the end of pregnancy and suckling stimulates PRL release and promotes continued milk production. Hypersecretion of PRL is more common than hyposecretion, seeing as hyposecretion is only observed when women are attempting to nurse. Hyperprolactinemia is the most frequent abnormality of the APG tumors.
	PPG – the two primary hormones are ADH and oxytocin
Antidiuretic hormone (ADH), released by the posterior pituitary gland (PPG), reduces the amount of urine that is formed. ADH targets the kidneys, modulates how much water is lost in the urine, and the secretion is inhibited by alcohol and diuretics. ADH is released in response to rising serum osmolality. This causes the kidneys to preserve water, helping to restore normal solute/water balance. ADH (and oxytocin!) is stored in the axon terminals of neurons of the hypothalamic-hypophyseal tracts, running through the infundibulum, ending in the PPG to be secreted into the capillaries of the inferior hypophyseal artery. Oxytocin is a strong stimulant of uterine contractions released during childbirth while also acting as a hormonal trigger for milk ejection. While they are stored in the PPG, ADH and oxytocin are both produced within the connecting hypothalamus. Specialized neurons, called neurosecretory cells, produce ADH in the paraventricular nuclei of the hypothalamus. This hormone is then transported down the axons of these neurons and stored in their axon terminals, which are located in the PPG. The PPG appears to only store and release neurohormones produces by the hypothalamus. The hormone is released from the axon endings when associated neurons fire action potentials (AP’s), and it passes down the axon to the axon terminals. By this logic, a blow to the head may cause diabetes insipidus by interfering with the normal transmission of nerve impulses to the PPG. Oxytocin release is an example of a positive-feedback mechanism.
Thyroid
The thyroid gland (TG) consists of the isthmus (median mass connecting the two lateral lobes), the follicles (the hollow sphere of epithelial follicular cells that produce the glycoprotein, thyroglobulin), the colloid (fluid of follicle lumen containing thyroglobulin plus iodine and is the precursor to thyroid hormone, TH), and the parafollicular cells (produce the hormone calcitonin, which is released when calcium levels rise in the body, no known effect). Iodinated thyroglobulin (the protein from which TH is produced), is stored in the lumen of the thyroid follicles until the TH is needed by the body. TH is the body’s major metabolic hormone and affects virtually every cell in the body. TH is found in two forms, T4 (thyroxine) and T3 (triiodothyronine). T4/thyroxine is the major form and consists of two tyrosine molecules with four bound iodine atoms and T3/triiodothyronine is the form that has two tyrosine molecules with three bound iodine atoms. T3 is the more active form of TH (10x more active), so T4 must be converted to T3 at the tissue level (via enzymes in the tissue removing one iodine) before it can be used. TH release is regulated by negative-feedback, as decreased TH levels stimulate the release of TSH. The rising TH levels (in response to the stimulation and increasing amount of TSH) provide negative feedback, so TSH release is inhibited. TRH is only utilized in situations of pregnancy or cold exposure in order to overcome the TSH’s negative feedback. Both TH’s are transported by thyroxine-binding globulins (TBG’s). TH functions by entering the target cells and binding to intracellular receptors within the nucleus, as it triggers transcription of various metabolic genes. The effect of TH is named the calorigenic effect, which includes increasing basal metabolic rate (BMR) and heat productive. TH is synthesized in seven easy steps: 1) Thyroglobulin is synthesized and discharged into the follicle lumen, 2) Iodide is trapped (Iodide ions I- are actively taken into the cells and released into the lumen), 3) Iodide is oxidized (electrons are removed, converting iodide into iodine I2), 4) Iodine is attached to tyrosine, mediated by peroxidase enzymes monoiodotyrosine (MIT, formed if only one iodine attaches) and diiodotyrosine (DIT, formed if two iodine’s attach), 5) Iodinated tyrosine’s link together to form T3 and T4 (1 MIT +  1 DIT = T3, 1 DIT + 1 DIT = T4), 6) Colloid is endocytosed by follicular cells (vesicle is then combined with a lysosome), and 7) Lysosomal enzymes cleave T3 and T4 from thyroglobulin (hormones are secreted into the bloodstream, mostly T4 is secreted but T3 is also, and, once again, T4 must be converted to T3 at the tissue level).
Hyposecretion of TH can lead to myxedema, which symptoms include low BMR, thick/dry skin, puffy eyes, chills, constipation, edema, mental sluggishness, and fatigue. This may be due to lack of iodine, which decreases TH levels. This decrease in TH triggers increased TSH secretion, triggering the thyroid to synthesize more and more unusable thyroglobulin. This build up causes an enlarged thyroid (aka the goiter). The low TH signals TSH release. Because the TSH release results in the unusable thyroglobulin, you get the buildup.
The most common form of TH hypersecretion is Grave’s disease. Grave’s disease is an autoimmune disorder in which the body produces abnormal antibodies that mimics TSH, stimulating TH release. Symptoms include elevated BMR, diaphoresis, tachycardia, palpitations, anxiety, and weight loss despite adequate intake.
The TG does secrete a hormone called calcitonin in response to a rise in blood Ca2+ levels; however, it DOES NOT have a known physiological role in humans. When administered at pharmacological doses (doses higher than normally found in the body), calcitonin has a bone-sparing effect and is given therapeutically to patients with osteoporosis or Paget’s disease.
Parathyroid
The 4-8 parathyroid glands (PTG) are located on the posterior aspect of the thyroid gland in separate areas. The PTG secretes parathyroid hormone (PTH) and PTG is the single most important hormone controlling calcium balance in the blood. Decreasing blood Ca2+ levels triggers PTH release and increasing Ca2+ levels inhibit PTH release. PTH promotes bone resorption to release Ca2+ into the blood, inhibits excretion of Ca2+ in the urine, and stimulates the synthesis of Calcitriol, which in turn increases absorption of Ca2+ from out diet. PTH’s targets are the skeleton, kidneys, and intestines. PTH functions by stimulating osteoclasts to digest bone matrix and release Ca2+ into the blood, enhances reabsorption of Ca2+ and secretion of phosphate (PO43-) by kidneys, and promotes activation of vitamin D by kidneys (which leads to increased absorption of Ca2+ by intestinal mucosa). Note that inhibition of calcitonin synthesis is NOT a function of PTH. Hyperparathyroidism (caused by tumors) causes bone to soften and deform (due to calcium leaching from the bones), depresses the nervous system and contributes to the formation of kidney stones (due to elevated Ca2+ levels), and, in severe cases, can result in easily fractured bones (Osteitis fibrosa cystica). Hypoparathyroidism (caused by gland trauma or removal) can cause hypocalcemia, resulting in muscle cramping, respiratory paralysis, and subsequent death.
The adrenal glands (AG) are located just on top of the kidneys and are essentially two glands in one: the adrenal cortex (AC) and the adrenal medulla (AM).
The AD consists of three layers of glandular tissue that synthesizes and synthesizes and secretes several different hormones. The AC produces >24 hormones that are classified as corticosteroids. Note that steroid hormones are not stored in the cells of the AC, so the rate of release depends on the rate of synthesis. The three layers of the AC cells produce different corticosteroids, the zona glomerulosa (ZG) produces mineralocorticoids, the zona fasciculata (ZF) produces glucocorticoids, and the zona reticularis (ZR) produces gonadocorticoids.
The ZG mineralocorticoids regulate electrolyte concentrations (primarily Na+ and K+) in the ECF, essentially maintaining our fluid levels. Remember that Na+ affects ECF volume, blood volume, blood pressure, and other ion levels (including K+, H+, HCO3-, and Cl-). Also, K+ sets the resting membrane potential of the cells. The most important of the mineralocorticoids is aldosterone. Aldosterone stimulates Na+ reabsorption by the kidneys (the reabsorption of Na+ results in increased blood volume and blood pressure) and stimulates K+ elimination by the kidneys. Remember that Na+ wants to be going into the cell and K+ wants to be going out of the cell (NOKIA, sodium is out and wants to go in and vice versa), so aldosterone stimulates the synthesis and activation of the Na+-K+ ATPase transport pumps. Note that the effects of aldosterone are short-lived. The factors that regulate aldosterone secretion include the renin-angiotensin-aldosterone (RAA) mechanism, plasma concentration of K+, ACTH, and atrial natriuretic peptide (ANP). Note that the RAA, plasma K+, and ACTH methods increase aldosterone release while only ANP decreases aldosterone release. Hyperaldosteronism (caused by adrenal tumors) results in HTN and edema (due to excess Na+) and abnormal nonresponsive neurons and muscles (due to increased excretion of K+).
The RAA mechanism, in short, responds to decreased blood pressure by stimulating specialized cells in the kidneys that release renin into the blood. Renin cleaves off a part of a plasma protein, called angiotensinogen, which triggers the enzyme cascade resulting in angiotensinogen conversion to angiotensin II. Angiotensin II is a potent stimulator of aldosterone release.
Increased plasma K+ directly influences cells within the zona glomerulosa to release aldosterone. Meanwhile, decreased plasma K+ directly inhibits the zona glomerulosa from producing aldosterone.
ACTH can cause small increases of aldosterone during periods of increased stress.
ANP is secreted by the heart in response to hypertension. ANP blocks renin and aldosterone secretions into the blood. By blocking renin, aldosterone is also blocked, meaning that blood pressure will not be increasing. This is because Na+ reabsorption will not be increased in the kidneys, as will K+ elimination not being increased. This means that blood volume will not increase and therefore, blood pressure will not increase.
The ZF glucocorticoids influence metabolism of most cells and help us resist stressors, keep blood glucose levels relatively constant, and maintain blood pressure by increasing the action of vasoconstrictors. The primary glucocorticoid hormone is cortisol (hydrocortisone). Cortisol secretion causes increases in blood glucose (as well as increases in fatty acids and amino acids), gluconeogenesis (prime metabolic effect , formation of glucose from fats and proteins, which then encourages cells to use fatty acids for fuel so that glucose is preserved for the brain), and enhance vasoconstriction (causing increased blood pressure that would quickly distribute nutrients to other cells).
For decreased levels of cortisol, CRH is released (by the hypothalamus), which activates ACTH (by the APG), which then activates cortisol release (by the ZG in the AC). This results in decreased plasma glucose and Na+ levels. The primary disease associated with hyposecretion of cortisol (also needs hyposecretion of mineralocorticoids) is Addison’s disease (Signs and symptoms include bronzing of skin due to high ACTH levels triggering melanin production in melanocytes, weight loss, severe dehydration, and hypotension. Primary treatment option is corticosteroid replacement therapy.
For increased levels of cortisol, the CRH-ACTH cycle is inhibited through negative feedback. Cortisol secretion cycles are governed by patterns of eating and activity, but section can be interrupted in situations of acute stress (infection, physical or emotional trauma). The CNS is able to override the cortisol inhibition of CRH and ACTH, which can lead to more cortisol secretions. Some effects of increased cortisol/glucocorticoid levels, either due to long-term stress or genetic issues, include depression of cartilage and bone formation, inhibition of inflammation (through decreasing the release of inflammatory chemicals), depression of the immune system, and disruption of normal CV, neural, and GI functions. The primary disease associated with hypersecretion of cortisol is Cushing’s disease (caused by tumors on the pituitary, lungs, pancreas, kidneys, or adrenal cortex, or overuse of corticosteroids. Signs and symptoms include “moon” face and “buffalo hump”. Treatment options include removal of the tumor or discontinuation of the corticosteroids).
The ZR gonadocorticoids are weak androgens (male sex hormones) that are converted primarily into testosterone in tissue cells, though some are converted into estrogens. Gonadocorticoids may contribute to the onset of puberty and appears of secondary sex characteristics, sex drive in women, and source of estrogen in postmenopausal women. Hypersecretion of gonadocorticoids produces adrenogenital syndrome, or masculinizing effects. This isn’t readily apparent in adult males (as they are already masculinized), but is apparent in adult females (beard, masculine body hair, clitoral hypertrophy) and prepubescent males (sex organs and secondary sex characteristics mature early).
The AM consists of nervous tissue that is part of the sympathetic nervous system. The AM synthesize catecholamines, which is epinephrine and norepinephrine, which respond to short-term stressors (ie- fight-or-flight). Catecholamine’s cause vasoconstriction, tachycardia, hyperglycemia, and blood diverting primarily to the brain, heart, and skeletal muscles. Epinephrine is more of a stimulator of metabolic activities (ie. - bronchodilation, blood flow to skeletal muscles and heart), while norepinephrine has more of an influence of peripheral vasoconstriction and blood pressure. Catecholamines function in response to stress (from the sympathetic NS) activating the hypothalamus, which releases AP’s down the spinal cord. The AP then reaches the preganglionic sympathetic axons of the AM, which secretes epinephrine and norepinephrine. The epinephrine and norepinephrine reinforce other sympathetic responses to ready the body for exertion, including increasing heart rate, increasing blood pressure, redirecting blood flow away from nonessential organs, bronchodilation, conversion of glycogen into glucose (by the liver), and increasing metabolic rate. Hyposecretion of epinephrine and norepinephrine is not noticed, as they are nonessential to everyday life. Hypersecretion of epinephrine and norepinephrine leads to symptoms of uncontrolled sympathetic NS, including hyperglycemia, increased metabolic rate, tachycardia, palpitations, HTN, anxiety, and diaphoresis. Hypersecretion can be caused by a tumor on the medullary chromaffin cells. It should be noted that β-receptors that bind epinephrine and norepinephrine (adrenergic receptors) increase cAMP levels.
The pineal gland (PG), located towards the posterior-aspect of the hypothalamus, secretes melatonin, which had been derived from serotonin. Melatonin may affect timing of sexual maturation/puberty, day/night cycles, physiological processes that slow rhythmic variations (including body temperature, sleep, and appetite), and production of antioxidant/detoxification molecules within cells.
Other endocrine organs include the pancreas, gonads/placenta, adipose tissue, GI tract, heart, kidneys, bones (osteoclasts), skin, and thymus. To put it short, gonads secrete sex hormones (like the AC, but less), placenta secrete estrogen, progesterone, and human chorionic gonadotropin (hCG), adipose tissue secretes leptin (appetite control), resistin (insulin antagonist), and adiponectin (enhances sensitivity to insulin), GI tract secretes gastrin (stimulates release of HCl), ghrelin (stimulates food intake), secretin (stimulates liver and pancreas), cholecystokinin (activates pancreas, gallbladder, and hepato-pancreatic  sphincter), and incretins (enhances insulin release and inhibition of glucagon), heart secretes ANP (decreases blood sodium concentration to decrease blood pressure and blood volume), kidneys secrete erythropoietin (signals production of RBC’s) and renin (initiates RAA mechanism), osteoblasts in bones (activated by insulin) secrete osteocalcin (prods pancreas to secrete more insulin, restricts fat storage, improves glucose handling, reduces body fat), skin secretes cholecalciferol (precursor of vitamin D) and calcitriol (active form of vitamin D that helps absorb calcium from the GI), and the thymus (large in infants and children, shrinks with age) secretes thymulin, thymopoietins, and thymosins (may be involved in normal development of the T-lymphocytes in the immune response)
The pancreas has both exocrine (acinar cells producing enzyme-rich juice for digestion) and endocrine (alpha cells producing glucagon and beta cells producing insulin). Alpha cells stain darker, beta cells stain lighter, and acinar cells are external to the whole affair.
Glucagon is an extremely potent hyperglycemic agent that is triggered by decreased blood glucose levels, rising amino acid levels, or sympathetic NS response. Glucagon raises blood glucose levels by targeting the liver in order for it to breakdown glycogen into glucose (glycogenolysis), synthesizing glucose from lactic acid and other non-carbohydrates (gluconeogenesis), and releasing glucose into the blood.
Insulin is secreted when blood glucose levels increase. Insulin is initially synthesized as proinsulin, which is then modified when needed. Insulin lowers blood glucose by enhancing membrane transport of glucose into fat and muscle cells, inhibiting breakdown of glycogen into glucose, and inhibiting conversion of amino acids or fats into glucose. Insulin is not necessary needed for glucose uptake in the liver, kidneys, and brain, though it does play a role in neuronal development, learning, and memory. Growth factor hormones, such as insulin, bind to tyrosine kinase receptors without the use of a second-messenger. Insulin functions by binding to tyrosine kinase receptors, triggering cells to increase glucose uptake. Insulin also triggers cells to catalyze oxidation of glucose for ATP production (first priority), polymerize glucose to form glycogen, and convert glucose into fat (particularly in adipose tissue). Some factors that influence insulin release include elevated blood glucose levels (primary stimulus), rising blood levels of amino acids and fatty acids, release of ACh by parasympathetic nerve fibers, hormones glucagon, epinephrine, GH, thyroxine, and glucocorticoids, and somatostatin and sympathetic NS inhibiting insulin release. Hypersecretion of insulin caused hypoglycemia (symptoms include anxiety, confusion, decreased mentation, and possibly death. The primary treatment option is ingestion of glucose).
The biggest insulin imbalance is DM; DM1 is the hyposecretion of insulin while DM2 is the hypoactivity of insulin. The three signs of DM are polyuria (large urine output, caused by glucose acting as an osmotic diuretic), polydipsia (large thirst, caused by water lost due to polyuria), and polyphagia (large hunger, caused by cells not up-taking glucose so they “starve”). When glucose cannot be used, as in DM, fats are utilized, causing hyperlipidemia (high levels of fatty acids in the blood). The metabolism of these fatty acids results in the formation of ketones, which are acidic. The buildup of ketones cause ketoacidosis, which causes tachypnea, disrupted cardiac activity and O2 transport, and severe depression of the NS that could possibly lead to coma and death. It should be noted that low-levels of osteocalcin are typically present in DM2.


























Blood
Blood is a part of the CV system and is the life-sustaining transport vehicle of the CV system. Functions of blood include transport (O2 and nutrients to body cells, metabolic wastes to lungs – CO2 – and kidneys –other – for elimination, hormones from endocrine organs to target organs), regulation (body temperature by absorbing and distributing heat, normal pH using buffers and alkaline reserves of bicarbonate ions, adequate fluid volume within the circulatory system), and protection (preventing blood loss through the use of proteins and PLT’s, preventing infection through carrying agents of immunity – antibodies, complement proteins, and WBC’s). The main characteristics of blood include: being the only fluid tissue within the body, containing ~five-million erythrocytes (RBC’s) per microliter, has a pH usually between 7.35-7.45, tastes metallic/salty, and is more viscous than water. Blood is considered a connective tissue as it develops from the mesenchyme. Blood with high-oxygen levels is a scarlet-red color while blood with low-oxygen levels is a dark-red color. The matrix is a nonliving fluid (called plasma) which suspends the living blood cells (called formed elements including RBC’s, WBC’s and PLT’s). A centrifuged sample of blood results in three layers: the bottom ~45% is the RBC’s, the middle <1% is the WBC’s + PLT’s/buffy coat, and the top 55% is plasma. WBC’s are the only formed elements that are complete, as RBC’s have no nuclei/other organelles and PLT’s are just cell fragments. Most blood cells originate in the red bone marrow and do not divide (aka stuck in the G1 phase).
RBC’s make up ~45% of whole blood and are small (7.5 μm diameter x 2.5 μm height) that aides in gas transport. RBC’s have a biconcave disc shape, are anucleate, and have essentially no organelles (including no mitochondria). RBC’s are able to bend and twist to fit through vessels as they are held in shape by flexible proteins (spectrin) that allow the cell to bend, twist, and cup, but which will return it to its normal shape. This facilitates the movement of RBC’s through capillaries that are sometimes smaller than they are. RBC’s are dedicated to respiratory gas transport. RBC’s are filled with hemoglobin (HGB) that is utilized in gas transport. There are three features of RBC’s that make for efficient gas transport: 1) the biconcave shape offers a huge surface area relative to the volume for gas exchange, 2) HGB makes up ~97% of the cell volume (not including water), and 3) RBC’s have no mitochondria (meaning that O2 is not used aka ATP production is anaerobic).
There are around ~250 million HGB molecules in each RBC. HGB is composed of four protein/polypeptide chains and four connected (to the proteins) heme groups. Four oxygen molecules can be transported by one HGB molecule. Each iron atom centered in the heme group can bind reversibly with one oxygen molecule. O2 loading (in the lungs) produces oxyhemoglobin (which is ruby red). O2 unloading in the tissues produces deoxyhemoglobin (aka reduced HGB, which is dark red). Around 20% of CO2 in the blood (from the tissues) binds to HGB, CO2 loading in the tissues, producing carbaminohemoglobin (which is what gives blood its red color). The globulin polypeptides/proteins/amino acids of the globulin are the part of the HGB molecule that binds CO2 for transport.
A hematocrit (HCT) is the percentage of erythrocytes (RBC’s) in a whole blood sample. In a centrifuged sample of blood, fibrinogens, electrolytes and albumin should be included in the plasma portion of the sample. PLT’s are dense enough that they should be in the buffy coat layer of the centrifuged blood. In a person that was severely dehydrated, you would expect to see higher blood viscosity, higher HCT, and lower plasma levels (immunity would not be affected).
The hematopoietic stem cell (hemocytoblast) is the stem cell for all blood-formed elements. This process is known as hematopoiesis and occurs in the red bone marrow. The red bone marrow is composed of reticular CT and blood sinusoids (which is the location that new blood cells enter the blood vessels). Hormones and growth factors are the factors that push the stem cell toward a specific pathway of blood cell development. Decreased RBC’s leads to tissue hypoxia (poor oxygen transport) while elevated RBC’s leads to increased blood viscosity. The balance between RBC production and destruction depends on hormonal controls (stimulated by EPO) and dietary requirements.
Erythropoietin (EPO) is the primary hormone that simulates RBC production (also causes RBC’s to mature faster). It is important to notes that erythropoietin is NOT a plasma protein. EPO is produced within the kidneys (some from the liver) in response to hypoxia. In hypoxic-situations, oxygen-sensitive enzymes in the kidney cells cannot degrade the hypoxia-induced factor (HIF), causing the accumulation that triggers EPO synthesis. Common causes of hypoxia include decreased RBC levels (due to hemorrhage or increased destruction), insufficient HGB per RBC (ie. - iron deficiency), or reduced availability of O2 (elevated altitudes, lung-related disease). In situations with too many RBC’s or oversaturation of oxygen, EPO production is inhibited. There is always small amount of EPO present within the blood to maintain baseline BMR. EPO stimulates the developmental process of RBC formation (aka erythropoiesis). EPO does this by targeting the bone marrow, specifically the red bone marrow. This is the site of blood cell production and is stimulated by EPO. Erythropoiesis can be triggered by EPO, the presence of testosterone, or low blood-oxygen levels. Increased oxygen levels in the blood DOES NOT trigger erythropoiesis. It is important to note that reticulocyte count indicates the rate of RBC formation. Erythropoiesis occurs in eight simple steps over the course of 15 days: 1) hematopoietic stems cells (transform into myeloid stem cells), 2) myeloid stem cells (transform into proerythroblasts), 3) proerythroblasts (divide many times, transforming into basophilic erythroblasts), 4) basophilic erythroblasts (synthesize many ribosomes, which stain blue), 5) polychromatic erythroblasts (synthesize large amounts of red-hued HGB, now staining pink and blue), 6) orthochromatic erythroblasts (contain mostly HGB, appear mostly pink, ejects most of their organelles, and the nucleus degrades, causing the concave shape), 7) reticulocytes (still contain small amounts of ribosomes), and 8) mature erythrocytes (ribosomes degrade, transforming the reticulocyte into the mature RBC).
RBC’s typically last for ~120 days. Being that RBC’s are anucleate, they are unable to synthesize new proteins, grow, or divide. Older RBC’s are more fragile, HGB degenerates, and they can are easily trapped in smaller capillaries (mostly in the spleen). Macrophages within the spleen engulf and breakdown dying RBC’s, during which iron, heme, and globulin are separated. Iron binds to ferridin or hemosiderin within body cells are and stored for reuse. Heme is degraded down into the yellow-pigment bilirubin. Bilirubin is secreted by the liver into the intestines, where it is then degraded into the pigment urobilinogen. Urobilinogen is transformed into the brown-pigment stercobilin that leaves the body through feces. Globulin is metabolized into amino acids that are then released back into circulation. Iron reused, globulin broken down then reused, heme broken down then released. Most RBC disorders are classified as either anemia (abnormally-low O2-carrying capacity that is too low to support normal metabolism) or polycythemia (abnormal excess of RBCs that increases blood viscosity causing poor blood flow).
Anemia is where there is abnormally-low O2-carrying capacity that is too low to support normal metabolism.  Anemia is simply a sign of the problem, rather than the disease itself. Symptoms of anemia include fatigue, pallor, dyspnea, and chills. Anemia is categorized into three groups, based on cause: blood loss, decreased RBC production, and increased RBC destruction.
Blood loss anemia can further be classified into hemorrhagic anemia (due to rapid blood loss – severe wound – and treated with transfusion) and chronic hemorrhagic anemia (slight but persistent blood loss – from hemorrhoids or bleeding ulcerations, for example). Either way, treatment is to stop the bleeding.
Decreased RBC production can be due to iron-deficiency anemia (can be caused by hemorrhagic anemia, but also by low iron intake or impaired absorption), pernicious anemia (autoimmune disease that destroys stomach mucosa that produces the ‘intrinsic factor’ that is needed to absorb vitamin B12), renal anemia (caused by lack of EPO), or aplastic anemia (caused by the destruction or inhibition of red bone marrow, likely from sources such as drugs, chemicals, radiation, or viral). Iron-deficiency anemia produces microcyte-RBC’s that are small, pale in color, and cannot synthesize HGB due to the lack of iron. Treatment for iron-deficiency anemia is utilization of iron supplements. Pernicious anemia results from a vitamin B12 deficiency that may be the result of inadequate dietary intake of vitamin B12 or the lack of intrinsic factor (produced in the stomach). Intrinsic factor is required for absorption of vitamin B12 in the GI. Vitamin B12 is needed to help RBC’s divide. Without the B12, the RBC’s cannot divide, resulting in large macrocyte-RBC’s. Treatment for percutaneous anemia includes B12 administration through IM or intranasal means. Renal anemia often accompanies CKD as the kidneys cannot produce enough EPO. Treatment for renal anemia is typically the administration of synthetic EPO. The true cause of aplastic anemia is typically unknown, and results in all formed element cell-lines being affected. This results in anemia, as well as clotting and immunity deficits. A person exhibiting suppression of immunity and clotting disorder, as well as low oxygen-carrying capacity, is likely suffering from aplastic anemia. Treatment options for aplastic anemia are utilization of transfusions (short-term) and transplantation of stem cells (long-term).
Increased RBC destruction is mostly due to sickle-cell anemia (caused by a genetic mutation that results in the production of abnormal HGB, hemoglobin S – HbS). Sickle-cell anemia is the result from a change in just one of the 146 amino acids in a beta-chain of the globulin molecule. This alteration causes the beta-chains to link together under hypoxemic conditions, forming stiff so that HBS becomes spiky and sharp. This, in turn, causes the RBC’s to become crescent-shaped when they unload oxygen molecules or when the oxygen content of the blood is lower than normal. The stiff, deformed RBC’s rupture easily and tend to jam up in small blood vessels. These events interfere with oxygen delivery, leaving the victims gasping for air and in extreme pain. Bone and chest pain are particularly severe, and infection and stroke often follow. Acute sickle-cell crisis is treated with transfusions or the administration of nitric oxide to cause vasodilation. The one benefit of sickle-cell anemia is that these crescent-shaped RBC’s are unable to carry malaria, increasing chance for surviving malarial infections. Long-term treatment options for sickle-cell anemia includes utilization of hydroxyurea (induces formation of fetal-HGB that will not sickle), stem cell transplants, gene therapy, and administration of nitric oxide (for vasodilation).
Polycythemia is the abnormal excess of RBCs that increases blood viscosity causing poor blood flow. Potential causes for this include polycythemia vera (a bone marrow cancer that leads to excess RBC’s), secondary polycythemia (caused by low oxygen levels), and blood doping (removing, storing, and reinfusing RBC’s prior to competition to increase O2 levels to increase stamina). Polycythemia vera causes HCT to increase (potentially to drastic levels) and the primary treatment option is “therapeutic phlebotomy”. Secondary polycythemia is can be caused by elevated altitudes or increased EPO production.
Leukocytes (WBC’s) are the only formed element that is a complete cell with a nuclei and organelles. WBC’s make up <1% of the total blood volume and they function as a defense system against disease. WBC’s are able to leave the capillaries via diapedesis and can travel through the tissue spaces by amoeboid motion and positive chemotaxis (movement towards a chemical gradient). Leukocytosis refers to an elevated WBC-level and is a normal response to infection. WB’s are divided into two groups: granular/granulocytes (visible cytoplasmic granules, phagocytic, NEB) and agranular/agranulocytes (nonvisible cytoplasmic granules, LM). It is important to remember that neutrophils, eosinophils, and basophils are the granular WBC’s while lymphocytes and monocytes are agranular. Eosinophil and basophil granules absorb strongly, but they absorb different colors. The granules in neutrophils absorb weakly. Being that the WBC’s appears as the buffy coat in the theoretical centrifuge, the WBC’s stack in this order: plasma, NEBLM, RBC’s. Neutrophils have a 3+-lobed nucleus, eosinophils have a two-lobed nucleus that stains red, basophils have a two-lobed nucleus that stains purple-black, lymphocytes have a spherical nucleus, and monocytes have a kidney-shaped nucleus with a large cytoplasm.
Neutrophils act as our body’s bacteria killers and would dramatically increase in number during a bacterial infection. Neutrophils are active phagocytes and they are especially partial to ingesting bacteria. Neutrophils kill microbes via a process called respiratory burst, where the cell synthesizes a potent oxidizing substance (ie. - bleach or hydrogen peroxide). Neutrophils utilize hydrolytic enzymes or antimicrobial proteins (defensins) within the granules that merge with the phagosome to form “spears” that pierce holes into the membranes of ingested molecules. Neutrophils stain with both acidic and basic dyes.
Eosinophils play a role in defense against allergens, asthma-like symptoms, and immune-response modulators. The eosinophilic nucleus has two loves connected by a broad-band, resembling ear muffs. The red-staining granules contain digestive enzymes that break down the surfaces of parasites as well.
Basophils are similar to mast cells (CT cells) in that they both contain granules that release histamine to mediate an inflammatory response. The histamine acts as a vasodilator and attracts WBC’s to the enflamed areas. The nuclei of basophils are a deep purple with 1-2 constrictions, and they contain large, purplish-black granules that contain the histamine.
Lymphocytes are large, dark purple, and contain circular nuclei with a thin rim of blue cytoplasm. Lymphocytes are typically found in lymphoid tissue, but a few do circulate in the blood. Lymphocytes are divided into two types, T-lymphocytes (T-cells: act against virus-infected and tumor cells) and B-lymphocytes (B cells:  give rise to plasma cells which produce antibodies).
Monocytes have an abundant, pale blue cytoplasm and a dark purple-staining U- or kidney-shaped nucleus. Monocytes function by leaving circulation, entering the tissues, and differentiating into macrophages as actively phagocytic cells that are crucial against viruses, intracellular bacterial parasites, and chronic infections. Additionally, monocytes activate lymphocytes in order to mount a humoral immune response by producing antibodies.
Just to go over everything, neutrophils have a multi-lobed nucleus with pale red and blue cytoplasmic granules, eosinophils have a two-lobed nucleus with red cytoplasmic granules, basophils have a two-lobed nucleus with purplish-black cytoplasmic granules, lymphocytes have a spherical nucleus and a thin-rim of pale-blue cytoplasm, and monocytes have a kidney-shaped nucleus and an abundant pale-blue cytoplasm.
All WBC’s originate from hemocytoblast stem cells that then branch into two pathways: lymphoid stem cells (producing lymphocytes) and myeloid stem cells (producing all other elements, NEBM). The process of producing WBC’s (leukopoiesis) is stimulated by two types of chemical messengers interleukins (that come from red bone marrow) and mature WBC’s (through the action of colony-stimulating factors – CSF’s – named for the WBC type they stimulate, granulocyte-CSF stimulate granulocytes).
Granulocyte (NEB) production occurs in five steps: 1) myeloblasts (arise from myeloid stem cells), 2) promyelocytes (accumulate lysosomes), 3) myelocytes (accumulate granules), 4) band cells (nuclei form the curved arc), and 5) mature granulocyte (nuclei become segmented before being release into the blood). It should be notes that there are ten times more mature granulocytes (stored in bone marrow) than is present in the blood.
Agranulocyte (LM) production occurs in two different ways (recall that monocytes are derived from myeloid stem cells while lymphocytes are derived from lymphoid stem cells). There are two types of lymphocytes (T and B). ‘T-lymphocyte precursors’ give rise to ‘immature T-lymphocytes’ that mature within the thymus, while ’B-lymphocyte precursors’ give rise to ‘immature B-lymphocytes’ that mature within the bone marrow.

Many hematopoietic hormones (EPO and CSF’s) are used in clinic as they can stimulate the bone marrows of cancer patients receiving chemotherapy/stem cell transplants and are used to increase the protective immune responses of AIDS patients.
The over production of WBC’s (primarily abnormal) can be seen in people with leukemia or infectious mononucleosis while abnormally-low amounts of WBC’s (aka leukopenia) can be seen in people using anticancer drugs and glucocorticoids.
Leukemia is a cancerous condition in which there is an overproduction of immature, abnormal, non-functional WBC’s (usually involving clones of a single abnormal cell) that are non-functional. The immature, abnormal, non-functional WBC’s flood the blood stream, crowding out other cells lines, and leading to anemia and bleeding. Death associated with leukemia typically occurs from internal hemorrhage or overwhelming infections.  The two types of leukemia are acute (quickly-advancing leukemia derived from stem cells, primarily affecting children) and chronic (slow-advancing leukemia involving proliferation during later cell stages, more prevalent in older people). The name of the leukemia refers to the abnormal WBC-clone involved (myeloid leukemia involves myeloblast descendants while lymphocytic leukemia involves lymphocytes). The treatment options for leukemia include irradiation, anti-leukemic drugs, and stem cell transplants.
Infectious mononucleosis is a highly-contagious viral disease (typically seen in young adults) caused by the Epstein-Barr virus. This particular infection results in a high number of typical agranulocytes that causes lymphocytes to become enlarged. The reason it is named mononucleosis was because it was first thought to be caused by monocytes.
The plasma makes up the greatest portion of whole blood by volume and is made of ~90% water. Plasma contains >100 dissolved solutes, which includes nutrients, gases, hormones, wastes, proteins, and inorganic ions. Plasma proteins are the most abundant of the solutes. It is important to note that plasma proteins remain within the blood and are not taken up by cells. These proteins are primarily produced in the liver. Types of plasma proteins include albumin, globulins, and fibrinogen.
Albumin makes up ~60% of the plasma proteins and functions as a carrier of other molecules, acts as a blood buffer, and contributes toward plasma osmotic pressure.
Alpha globulins are primarily concerned with the transport of metal ions and fat-soluble vitamins.
Gamma globulins (aka immunoglobulins/antibodies) are a part of the immune response.
Fibrinogen comprises ~4% of plasma and is the main contributor in the process of blood clotting. By this logic, the loss of fibrinogen within the plasma would most likely cause loss of blood clotting.
Platelets (PLT’s) are cell fragments from larger megakaryocytes and contain several chemicals that are involved in the clotting process (including serotonin, calcium, enzymes, ADP, and platelet-derived growth factor – PDGF). PLT’s are known to have blue-staining outer regions with purple granules. PLT formation (thrombopoiesis) is stimulated by thrombopoietin. PLT’s are formed in the myeloid line from megakaryoblasts (stage I megakaryocytes), during which mitosis occurs but there are no cytokines, which results in large stage IV megakaryocyte cells with multi-lobed nuclei. Megakaryocytes place PLT’s in the blood by passing through the wall of the sinusoidal capillaries (with large openings in their walls) in the bone marrow, where they then break off into the PLT fragments. To put it shortly, PLT’s are formed through 1) hematopoietic stem cell (hemocytoblast), 2) megakaryocyte (stage I megakaryocyte), 3) stage II/III megakaryocyte, 4) stage IV megakaryocyte, and 5) degradation into PLT’s.
Hemostasis is important for and it leads to the stoppage of bleeding. The hemostasis response is fast, localized, and controlled. Hemostasis requires and involves clotting factors and substances released by PLT’s and the damaged tissue. The three steps involved with hemostasis are 1) the vascular spasm, 2) PLT-plug formation, and 3) coagulation (blood clotting).
During the vascular spasm, the injured vessel vasoconstricts (in response to direct injury to the vascular smooth muscle, chemicals released by endothelial cells and PLT’s, or pain reflexes). The vasoconstriction is most effective in small blood vessels as large blood vessels are just logistically harder to plug. This vasoconstriction can significantly reduce blood flow until other mechanisms have kicked in.
During the PLT-plug formation, PLT’s are able to adhere to exposed collagen fibers (exposed when the vessel had been damaged ). PLT’s are not able to stick to the intact endothelial cell or vessel walls because the collagen is not exposed. Additionally, prostacyclins and nitric oxide are secreted by endothelial cells to prevent PLT’s from sticking to the walls. When they are activated, PLT’s swell, become spiky and sticky, and release chemical messengers ADP (causing more PLT’s to stick and release contents) and serotonin and thromboxane A2 (enhancing the vascular spasm and PLT aggregation). Because of this, this process is a positive-feedback cycle, as the more PLT’s that stick, the more chemicals that are released, causing more PLT’s to stick and release more chemicals. PLT-plugs are fine for smaller vascular tears, but larger breaks in vessels require the final step.
Coagulation (blood clotting) reinforces the PLT-plug utilizing fibrin threads and is effective in sealing larger vascular injuries. During this process, the blood is converted from a liquid into a gel utilizing a series of reactions using clotting factors (pro-coagulants, mostly plasma proteins numbered I-XIII in order of discovery). Most clotting factors are plasma proteins synthesized by the liver and they are numbers I-XIII (named according to their order of discovery). All clotting factors (except tissue factor) normally circulate in blood in an inactive form until mobilized. Although vitamin K is not directly involved in coagulation, this fat-soluble vitamin is required for synthesizing four of the clotting factors. Coagulation occurs in three phases.
During phase I, there are two pathways to the prothrombin (clot-forming) activator, initiated by either intrinsic or extrinsic pathways (usually both). PLT chemicals within the blood initiate the intrinsic pathway, but external (to the blood) tissue factors released from damaged endothelium start the extrinsic pathway for coagulation in motion. The intrinsic pathway is triggered by negatively-charged surfaces, such as activated PLT’s, collagen, or even the glass of a test tube. The extrinsic pathway is triggered by exposure to tissue factor (TF, factor III) and bypasses several steps of the intrinsic pathway, making it faster. Either way, the clot-forming activation is triggered by the tissue-damaging event which then involves a series of pro-coagulants, and cascades and ends with the activation of factor X. Factor X then complexes with Ca2+, PF3 (PLT factor 3), and factor V to form the prothrombin (coagulation-forming activator).
During phase II, the prothrombin (clot-forming) activator catalyzes the transformation of prothrombin into the active enzyme thrombin.
During phase III, the fibrin mesh is formed. Thrombin converts the soluble fibrinogen into fibrin. The fibrin strands form the structural basis of the clot by causing plasma to become gel-like in order to catch formed elements. Meanwhile, thrombin (still present) + Ca2+ activates factor XIII (fibrin-stabilizing factor) which cross-links the fibrin and strengthens and stabilizes the clot.
Anticoagulants are factors that are normally present and dominate within the blood in order to inhibit coagulation.
For clot retraction and fibrinolysis, the clot must be stabilized and removed when the damage has been repaired.
During clot retraction, actin and myosin within the PLT’s contract, pulling on the fibrin strands. This contraction squeezes serum (anything that isn’t clotting proteins) out from the clot, and also draws the ruptured blood vessel edges together. It is important to note that the vessel is healing even after the clot retraction has occurred. PDGF is released by PLT’s in order to stimulate the division of the smooth muscle cells and fibroblasts to rebuild the blood vessel wall. Vascular endothelial growth factor (VEGF) stimulates the endothelial cells, ordering them to multiply and restore the endothelial lining.
During fibrinolysis (process whereby clots are removed after repair has been completed), plasminogen (plasma protein that has been trapped within the clot) is converted into plasmin, the enzyme that digests the fibrin in the clot. The plasmin is the true enzyme that removes the unneeded clot after healing has occurred. Tissue plasminogen activator (tPA), factor XII, and thrombin all play a role within the conversion process, from plasminogen into plasmin.
There are some factors that limit normal blood clot growth. The swift removal and dilution of the clotting factors and inhibition of the activated clotting factors limits the size of the clot while only a limited amount of thrombin is restricted to the blood clot by fibrin threads (preventing the clot from getting too big or escaping into the bloodstream). Anti-thrombin III inactivates any unbound thrombin that may have escaped into the bloodstream while heparin (present within the basophils and mast cells) inhibit thrombin by enhancing anti-thrombin III.
There are some other factors that prevent any undesirable clotting, mostly through preventing PLT adhesion. The smooth endothelium of the blood vessels prevents PLT’s from clinging onto the walls of the blood vessels. Additionally, endothelial cells secrete anti-thrombic substances (like nitric oxide and prostacyclin). Finally, vitamin E quinone (formed when vitamin E reacts with oxygen) is a potent anticoagulant.
There are two major types of disorders associated with blood-clotting, thromboembolic (resulting in undesirable clot formation) and bleeding disorders (abnormalities that prevent normal clot formation). Situations of disseminated intravascular coagulation (DIC) involve both types of disorders.
In thromboembolic conditions, thrombi and emboli are formed (thrombus – clot in unbroken blood vessel blocking circulation leading to tissue death, embolus – thrombus freely-floating in the blood, embolism –embolus obstruction a vessel). The risk factors associated with this are atherosclerosis, inflammation, slowly-flowing blood, or blood stasis from immobility. Anticoagulant drugs are used to prevent undesirable clotting, which includes aspirin (anti-prostaglandin that inhibits thromboxane A2), heparin, and warfarin and direct oral anticoagulants (interferes with the action of vitamin K).
There are several bleeding disorders, including thrombocytopenia, liver dysfunction, and hemophilia
Thrombocytopenia is known to produce petechiae (as a result of spontaneous widespread hemorrhage), can be caused by conditions that suppress/destroy bone marrow, and can be caused by having a low number of circulating PLT’s.
Liver dysfunction has been heavily associated with bleeding disorders because the liver is the primary sources for the clotting factors, which are required in sufficiency numbers for coagulation. Bleeding disorders can occur when the liver cannot synthesize the usual supply of pro-coagulants. The cause of impaired liver function includes vitamin K deficiency, hepatitis, or cirrhosis. Liver disease can also prevent the liver from producing and secreting bile, which is needed in order for the intestines to absorb fat and vitamin K.
Hemophilia includes several hereditary bleeding disorders associated with deficiencies of some of the clotting factors (A due to factor VIII deficiency, B due to factor IX deficiency, C due to factor XI deficiency).
In DIC conditions, there is widespread clotting and severe bleeding. The widespread clotting occurs in intact blood vessels that block blood flow. The severe bleeding follows because residual blood I unable to clot because the clotting factors have been depleted. DIC typically occurs in septicemia, incompatible blood transfusions, or pregnancy-related complications.
The CV system minimizes the effects of blood loss by reducing the volume of the affected blood vessels and by stepping up the production of RBC’s. However, the body can only compensate so much for blood loss. The loss of 15-30% of the blood volume loss causes pallor and weakness while >30% blood volume loss can result in potentially fatal severe shock. In order to restore blood volume, it must be replaced with NS/LR that mimics the electrolyte composition. Replacing lost blood volume with an isotonic saline solution lowers the patient’s hematocrit and does improve volume, but does not restore the oxygen-carrying capacity of the RBC’s. Whole-blood transfusions are used only when blood loss is rapid and substantial. Infusions of p-RBC’s (no plasma or WBC’s) are preferred in order to restore oxygen-carrying capacity by repleting RBC’s. A patient could be given p-RBC’s in addition to the NS because p-RBC’s contain oxygen-carrying HGB, so they are able to carry oxygen to the tissues. While the NS replaces lost blood volume, it cannot replace the HGB in the lost RBC’s. Human blood groups of donated blood must be determined because transfusion reactions can be fatal (blood typing determines groups).
Remember now that RBC membranes bear many different antigens (antigens are anything perceived as foreign by the body that could generate an immune response).  RBC antigens are referred to as agglutinogens because they promote agglutination. Ergo, agglutinogens are glycoproteins that are found on the surface of RBC’s. Mismatched transfused blood is perceived as foreign and may be agglutinated and destroyed, which is a potentially fatal reaction. The most important of the agglutinogens are ABO and Rh, which is where we derive the ABO blood types with +/-.
The AO blood groups are based on the presence or absence of two agglutinogens (A/B) on the surface of the RBC’s. Type A blood only has the A-agglutinogen and the same rules will apply for type B. Type O blood, which does not contain either A or B agglutinogens, will not cross-react with the anti-A agglutinins found in a recipient person with type B blood. This means that type O blood can be safely given to a recipient with type B blood. Type AB blood will have A- and B-agglutinogens, so they are able to receive all three types of blood, making them the “universal recipient”, because neither anti-A or anti-B antibodies (agglutinins) are present. This is a bit of a misnomer as type AB blood can still reject from the other agglutinogens.
To clarify, a person with type B blood can only give blood to people of the type AB and B blood. The type O recipients has anti-A and anti-B antibodies in their plasma, which would produce a transfusion reaction with the B-antigens from the type B blood. Just to sum it all up, type AB blood will coagulate (and have) with both anti-A (A blood) and anti-B (B blood) agglutinogens, type A will only coagulate (have) with anti-A agglutinogens, type B will only coagulate (have) with anti-B agglutinogens, and type O will coagulate (have none) with neither anti-A or anti-B agglutinogens.
The Rh blood groups are based on the presence of the D-Rh antigen. The most common is Rh+, meaning Rh- people will react to the presence of the Rh antibodies, while RH+ people would not. Additionally, Rhogam is a medication that can be used so that an Rh- mother would not react to a fetus that was Rh+.
To sum this up, a person with A+ blood could receive A+, A-, O+, and O- blood types safely.
Transfusion reactions occur if mismatched blood in infused. This is where the donor’s cells are attacked by the recipient’s plasma agglutinins, which agglutinate and clog the small vessels, causing rupture and releasing HGB into the bloodstream. This results in diminished oxygen-carrying capacity and decreased blood flow beyond the blocked vessel. Additionally, HGB in the kidney tubules can lead to renal failure.