circulation/study guide/ blood

i. DNA polymerases are responsible for the process of DNA repair during replication. Enzymes identify errors in the sequences and removes the incorrect nucleotide and replaces it with a correct one

Normally spontaneous or consequence of chemical or radiation induced injury;

1. Reactive oxygen species
2. Chemical mutations from environmental or occupational exposures
3. Radiation [sun exposure]
4. Failure of cellular protective strategies

1. Silent: change in genotype dose not change phenotype
2. Missense: altering a nucleotide changes one amino acid in the protein product
3. Nonsense: altering a nucleotide inserts a premature stop codon, protein is truncated and nonfunctional

1. Insertion [addition of base pairs] mutations alters reading frame and amino acid sequence

2. Deletion [deletion of base pairs] mutation alters reading frame and amino acid sequence

serum phenylalanine at 3 days old

● early intervention with a diet limited in phenylalanine can avoid most of the serious consequences of PKU, so early detection is critical→ autosomal recessive

i. autosomal dominant: mutation of the FBNI
1. Tall stature, aortic dilation and dissection, scoliosis, joint hypermobility, arachnodactyly, pectus excavatum, and mitral valve proplapse

50% chance of male or female child being affected

i. all female children are affected; no male children affected

50% chance of female child being carrier, 50% chance of male being affected

i. all female children are carriers, all male not affected

A genetic predisposition (sometimes also called genetic susceptibility) is an increased likelihood of developing a particular disease based on a person's genetic makeup. A genetic predisposition results from specific genetic variations that are often inherited from a parent.

● CAD is a progressive disorder resulting from the accumulation of atherosclerotic plaque in the coronary arteries and associated inflammation
○ multigenic/multifactoral disease
○ Family hx considered in risk calculations
○ Certain rare, single fene disorders increase risk and earlier onset
● Familiar hypercholesterolemia
● Familial defective apolipoprotein A
○ Relevant gene mutations:
● SLC01B1- increased myopathy risk from statins
● CYP2C19- prevent hepatic activation of clopidogrel

Residing in the nucleus, DNA must be replicated to create an identical copy before cells can undergo mitosis, producing identical daughter cells.
● Very stable; double helix; connected by hydrogen bonds between base pairs
● Backbone = deoxyribose sugars connected by phosphate bonds (polarity based on the free ends of the chain)
● DNA bases and base pairs
○ Adenine and thymine (two hydrogen bonds)
Guanine and cytosine (three hydrogen bonds

- If one parent has the disorder, there is a 50% chance he/she will pass on the abnormal copy of the gene to each offspring
- Sexes are equally likely to be affected/transmit the gene
- Affected person will have at least one affected parent
Diseases:
- Huntington
- Familial hypercholesterolemia
- Marfan syndrome
Neurofibromatosis

- If one parent is a carrier and the other is not affected (doesn't have disorder) and is not a carrier with each pregnancy there is a 50% chance that their offspring will be a carrier
- If both parents are carriers, but neither has the disorder there is a 25% chance the offspring will have the disorder, 50% chance they will be a carrier and 25% chance nonaffected noncarrier
- If affected individual mates with a nonaffected noncarrier, all of the offsprings will be carriers but none will be affected or nonaffected noncarriers
- If an affected individual mates with a carrier, there is a 50% chance their offspring will be affected and 50% chance they'll be a carrier

- Both sexes are equally affected

- Cystic fibrosis
- PKU
- Sickle Cell anemia
Tay sachs disease

- Rett syndrome
- Fragile X syndrome
X-linked hypophosphatemia

General term describing any chromosomal number other than the normal set of 46 chromosomes

○ Coarctation of the aorta
○ Scolosis
○ Hypothyroidism
■ The thyroid gland becomes under-active in about 10 percent of women
○ Diabetes (type II)
○ Osteoporosis

affects women- only has one X chromosome

● Small stature (shorter than average) with no growth spurt at puberty
● Poorly developed secondary sex characteristics
● Ovarian dysgenesis (no period or breast development without hormone therapy. Vagina and womb are totally normal though)
● Retardation of bone age (scoliosis, osteoporosis due to lack of estrogen)
● Webbed neck
● recurrent/frqeuent middle ear infection→ r/f hearing loss
● Good reading/verbal, poor math/memory/fine finger movement
● Lower or indistinct hair line
● Broad chest/widely spaced nipples
● Arms that turn out slightly at the elbow
● Heart murmur due to narrowing of aorta
● High blood pressure
● Minor eye problems (corrected with glasses)

● Epicanthal folds, slanted eyes, flat facial profile, simian crease in hands
● Growth failure
● Cognitive delay
● Congenital heart disease
● Malformed ears
● Big/protruding tongue
● Intestinal malformation
● Shortroad hands
● Wide gap between 1st and 2nd toe

● Aganglionic megacolon
● Acute lymphoblastic leukemia
● Early-onset Alzheimers

● Are developed from multipotent stem cells. It is stimulated by erythropoietin, stem cell factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin 3 (IL-3), BFR-Es proliferate into about 1,000 daughter cells that mature into colony-forming units-erythrocytosis (CFU-Es). Requires the proper cytokines, and availability of folate and vitamin B12.
● Tissue hypoxia (anemia, hemorrhage, chronic lung disease or high altitude ) stimulates increased erythropoietin production.
● Severe hypoxia may increase RBC production up to six time the normal level.
● Patients with chronic kidney disease have reduced erythropoietin production, which can lead to anemia.

100-120 days

● Fetal RBCs have a shorter life span- hemolysis contributes to neonatal jaundice→ 45-70 days
● Birth transition- RBC numbers decline, H and H nadir at 60 days, stimulating erythropoiesis
● Rapid growth contributes to high rates of iron deficiency anemia (breastfeeding is also a factor) and adolescence is also a time of increased anemia (diet change, period)
● Postnatal development of RBC includes: progressive decrease in cell size (MCV), drop in hgb concentration to a minimum between ages 2-6 months, followed by recovery to adult levels
● Older adults: decreased bone marrow cell numbers (fewer stem cells, fatty infiltration decreases functional tissue), thymus (involution- reduced lymphocyte production)

● State of iron imbalance due to chronic cytokine stimulation of the regulatory protein hepcidin
○ Hepcidin inhibits the iron transporter ferroportin—iron cannot leave cells
○ Iron builds up in gut cells and splenic macrophages and cannot reach the bone marrow
○ Findings include microcytic anemia (as in iron deficiency) and low reticulocyte count
○ Ferritin levels are normal, indicating normal total body iron stores

● Platelet glycoproteins allow: binding to von Willebrand factor, binding to fibrinogen, fibrin strands (aggregation)

● G protein-coupled receptors cause activation stimulated by ADP, thromboxane A2, and thrombin

○ Antibodies are produced against the platelet membrane glycoprotein or human leukocyte protein. Antibody binding "targets" the platelets for destruction by macrophages in the spleen and liver. First line therapy = steroids or IV immunoglobulin G (IVIG) infusions

● Most common cause is chronic inflammation: Metabolic syndrome (obesity, hypertension, truncal obesity, dyslipidemia, and insulin resistance ---- results in pro inflammatory markers) and Rheumatoid arthritis
○ Acute inflammatory conditions: influenza or pneumonia
○ Other conditions: Pregnancy, Oral contraceptives/hormone replacement (Estrogens increase liver synthesis of clotting proteins and decrease synthesis of protein S and AT-III (promotes clot formation), Cancer (Tumor cells have innately increased ability to initiate the clotting cascade)

Genetic disorder: Factor 5 Leiden
● Missense mutation- arginine replaced by glutamine
● The mutation alters factor V, making it resistant to cleave by activated protein c
● Significantly increased risk of venous thromboembolism, PE

○ Autoimmune disorder- antiphospholipid syndrome
● Often comorbid with other autoimmune disease (Lupus)
● Lab evaluations document antiphospholipid antibodies and other antibodies- relationship between these antibodies and hypercoagulability is unknown
● Spontaneous abortions in women of reproductive age, associated with preeclampsia and eclampsia
● Stroke and MI n men and women with no RF raises suspicion of this syndrome
● APS patients have elevated levels of antibodies against the phospholipid-binding plasma protein cardiolipin or β-glycoprotein 1 or both in addition to lupus anticoagulant antibodies

○ thrombocytopenia
● Plt # <150,000
● Superficial bleeding of increasing severity- petechiae, purpura, ecchymoses
● Other excess bleeding: gingival, epistaxis, menorrhagia
● Postinfectious: most common in children, spontaneous resolution
Autoimmune: more common in adults, managed with steroids or IV IgG

● results from heparin binding to platelet membranes
■ Immune response initiated- platelets are rapidly destroyed (they get eaten)
■ Resolves when heparin therapy stops- contraindication to future heparin treatment
■ ​​Results from the development of IgG antibodies to the platelet membrane complexes of heparin bound to platelet factor 4. This occurs within 5-10 days of exposure to heparin
■ The antibodies bind to the platelet surface stimulating platelet activation, with this activation there is an abundant release of procoagulants and consumption of platelets leading to thrombocytopenia.
■ Thrombocytopenia increases thrombosis risk. In HIT there is an increased production of thrombin as well as stimulation of inflammatory mediators. This cascade results in endothelial injury and increases the risk of large-vessel arterial or venous thrombosis.
■ Laboratory findings - platelets decreased, hallmark is an immunoassay for the antibodies to the heparin-platelet factor 4 complex or a function study looking at platelet aggregation when exposed to heparin.
■ Lifelong avoidance of all heparin produces.

○ affects platelet adhesion and factor VIII availability
● Genetic disorders- 6 subtypes, type I represent 70% of cases, autosomal dominant with incomplete penetrance
● Mechanism of clotting defect: decreased vWF levels- reduces platelet adherence to damaged endothelium, decreased factor VIII levels- reduces factor IX effectiveness
■ decrease in circulating vWF + decreased Factor VIII levels- increased bleeding time + clot formation is inadequate
● Findings: mucosal bleeding, epistaxis, suspected in excessive childhood bruising, menorrhagia
■ hematomas from mild to moderate trauma, excessive post partum bleeding
● Lab testing: ristocetin test stimulates vWF-platelet binding, agglutination abnormal in those with disease
● Roles - facilitating platelet aggregation at sites of vascular injury and helping to bind factor VIII to the platelet plug. - important step in the production of thrombin, fibrin, and eventual clot formation
● Defect on chromosome 12

Hemophilia A
■ Genetic disorder
■ Factor VIII deficiency, 4X more common than hemophilia B (Factor IX deficiency)
■ X-linked inheritance (carrier mother can have an affected son or carrier daughter, affected father can have carrier daughter)
■ 30% of cases are spontaneous mutations—no prior family history
■ Mechanism of clotting defect
● Factor VIII is required cofactor for factor IX activity
● Lack of factor VIII decreases reinforcing action of factor IX on the extrinsic pathway
● Severe factor deficiency associated with deep bleeds into joints (hemarthroses), hematomas, intracranial bleeds
■ Lab testing—factor levels, activated partial thromboplastin time (aPTT) prolongation
■ Management
● Factor replacement
● Therapies in development
● Factor VIII analogues
● Tissue factor pathway inhibitors
● Gene therapy

○ Endothelial injury
○ Venous stasis
○ Hypercoagulability

● Venous stasis and other states of low blood flow promote pooling of the blood, prolonged contact with endothelium that may reduce some of its anticlotting properties, and activation of the intrinsic clotting pathway
● Immobile during long trips, patients with reduced mobility secondary to an orthopedic procedure or prolonged illness

● Mural thrombi are thrombi that attach to the wall of a blood vessel and cardiac chamber. Mural thrombus occurrence in a normal or minimally atherosclerotic vessel is a rare entity in the absence of a hypercoagulative state or inflammatory, infectious, or familial aortic ailments
● Mural thrombi of the heart most commonly occur from atrial fibrillation, endocarditis, or post-myocardial infarction. Mural thrombi can be treated by acute thrombolysis or by long-term anticoagulation

one way valves

poor circulation, narrowing of vessels

Retinopathy (an eye condition); Nephropathy (a kidney condition); Atherosclerosis (hardening of the arteries); and Coronary/peripheral heart disease

Radiation, Chemicals, Free Radicals, Viruses, Heredity

● Genetic changes in a normally functioning cell that gradually transform the cell into a cancer cell. These result in the inability of body to restrain cell division and can lead to spread of the cancer cells around the body

● Uncontrolled proliferative signaling
● Evading growth suppressors
● Genomic instability
● Enabling cell immortality
● Resisting cell death
● Hijacking or generating blood supply sources for nourishment
● Acquiring invasive and metastatic abilities

○ favorable environment: decline in DNA reapir mechanisms, increased senescent cell number, decreased immune surveillance, longer exposure to environmental and endogenous sources
○ Accumulation of cellular mutations: mutations of DNA sequences in cells that reroute pathways regulating tissue homeostasis, cell survival or cell death. Cells more likely to accumulate mutations to develop one that triggers the development of cancer.
○ Decline in immune function: decline in thymic output of T- cells, decline in t cell and responsiveness contribute to reduced immune surveillance
○ Alterations in hematopoietic stem cells: cascade of changes in homeostasis with aging including a decline in organ function that affects the hematopoietic system, primarily stem cells. Hematopoietic reserves are depleted during aging and their ability to renew deteriorates, ability to differentiate into different cells is altered

● A paraneoplastic syndrome is a set of signs and symptoms that occur in people with a cancerous tumor. They develop when a malignant tumor releases a substance (hormone/protein) which affects a certain body system or when the body's immune system releases a substance (antibody) meant to kill the tumor but also damages healthy body cells (autoimmune response).

● ​​Paraneoplastic syndromes a constellation of clinical findings and effects from a primary malignancy. These syndromes are mediated by hormones secreted by the malignant cells and/or the immune response the hormones trigger.

● Endocrine-secreting tumor cells can induce symptoms of hyperparathyroidism or syndrome of inappropriate antidiuretic hormone (SIADH, look for CA [small cell carcinoma])

● Common is SIADH from tumor-produced vasopressin associated with lung cancers

● Hyper-parathyroid hormone-related protein - causes hypercalcemia and bone loss.

read notes

read notes; occurs due to chronic stress is inflammatory or injurious in nature that results in deregulated proliferation of cells

necrotic: cells swell, rupture, spill signals of tissue danger, initiate inflammation

apoptosis: cells shrink, small blebs containing contents break off, noninflammatory

autophagic: some cells digest their own contents, provide nutrients for other cells in the surrounding region, non inflammatory

Antibiotics kill healthy GI flora which leads to overgrowth of C. difficile bacteria. C. difficile causes pseudomembranous colitis by producing exotoxins which cause mucosal injury, inflammation, and diarrhea.

infection likely due to abx use and proton pump inhibitor use

● Innate immune response
○ Fast acting responding broadly to pathogen features not a specific pathogen.
○ Based on WBC and Scavenger cells that live within the tissues. These cells signal other immune cells with cytokines and chemokines recruiting them to the site of infection. Activated immune cells ingest pathogens
○ Moles of innate immunity include - proteins of the complement cascade - which directly attack and lyse bacterial.
○ These cells interact and communicate with cells involved in adaptive immune response.

○ Slower to respond but highly specific
○ A small number of these cells remain in the body (memory cells)
○ B- lymphocytes
○ Cytotoxic T lymphocytes
○ T-helper lymphocytes (T-helper cells).
○ Adaptive response produces immunological memory - vaccines are based upon this.

transformation of B cells into plasma cells that produce and secrete antibodies to a specific antigen.

Neutralization: Antibodies "neutralize" a pathogen by interfering with its ability to infect host cells. For example, when an antibody binds to the surface of a virus, it may impair the ability of the virus to attach to or gain entry into target cells, effectively inhibiting the infection.

Opsonization: Antibodies function as opsonins, which "tag" pathogens for destruction. Specifically, the formation of the antigen-antibody complex attracts and stimulates phagocytic cells that engulf and destroy the pathogen.

Complement: Antibodies can activate the complement system, which plays a role in both innate and adaptive immunity. The complement system is a sequential cascade of more than 30 proteins. With the help of antibodies, these proteins opsonize pathogens for destruction by macrophages and neutrophils, induce an inflammatory response with the recruitment of additional immune cells, and promote lysis (destruction) of the pathogen.

● IgE—monomer; responsible for allergic responses
● Least abundant(< 1%) IgE binds to mast cells and basophils interacting with its specific Receptor that is present on these innate cells.
● This binding triggers the release of preformed granules containing histamines and inflammatory molecules.
● Useful for eliminating parasites such as helminth worms.
● Very potent and cause tissue damage. It is associated with hypersensitivity type I diseases aka atopic diseases or allergies.

● Mechanisms are still poorly understood
● Genetic vulnerability is indicated by family history
● Tolerance by T cells is assessed during thymic development—potential autoreactive cells are detected and undergo apoptosis
● T regulatory cells can also suppress inappropriate immune responses
● Failure of tolerance leads to autoimmune disease
● Hypothetical mechanisms leading to autoimmunity
● Combination of genetic susceptibility and environmental triggers
● Early events cannot be clinically detected
● Progression to chronic tissue inflammation and fibrotic changes impairs function, causes pain, and target organ dysfunction
● Characteristic autoantibodies can be measured for diagnostic use
● General mechanisms in autoimmunity. The mechanisms underlying predisposition to autoimmune disease are not known, but family history is usually positive for members with one or more types of autoimmune disease. Against this background, it is thought that environmental exposures or prior infections can trigger autoreactivity. Autoantibodies are often present before any overt disease symptoms. Over time, the autoimmune response increases, with tissue damage resulting from immune and complement activation.

small size and membrane flexibility to easily flow through small capillaries

they bind to plasma trensferrin and are transported to the bone marrow for new RBC production

-healthy endothelium expresses many molecules that inhibit platelets and clotting cascade proteins

-plasmin system lyses clots once tissue has healed

-tissue factor pathway inhibitor blocks extrinsic pathway activity

-clotting cascade proteases are inactivated by antithrombin

-clotting cascade cofactors [V, VIII] are inhibited by the protein C/Protein S system

endothelium expresses:

nitric oxide
prostacyclin: inhibits platelet aggregation, vasodilator
proteoglycan: binds antithriombin III
thrombomodulin: activates protein C
tissue factor pathway inhibitor

the plasmin system breaks down clots when healing is occurred. tPa and uPa cleave the protein plasminogen in the circulation and bound in the clot to release plasmin. Plasmin is an enzyme that breaks down cross linked fibrin within the clot. Dissolving the clot and releasing fibrin breakdown products such as D-dimer, tpa, tissue plasminogen activator, uPa, urokinase type plasminogen activator

the circulating mediator AT-III binds to endothelial cell proteoglycans and inactivates proteases. PROTEIN c AND PROTEIN s WORK TOGETHER TO CLEAVE AND INACTIVATE PROTEINS VIII AND V- the required cofactors for factors IX and X

Chronic disease, severe infection, and the use of certain medications can all affect the body's blood-clotting ability

-Deliver blood from the heart to the tissues (conduit vessels)

-Distribute blood flow to the multiple parallel circuits of the systemic circulation

-Maintain blood pressure and blood flow during diastole

Wall tension (T) is increased by both pressure (P) and radius (r), but decreased by wall thickness (h).

the compensatory mechanism for increased vascular pressure is to increase wall thickness in blood vessels (vascular hypertrophy). This increase in wall thickness helps to offset the effect of increased pressure and decrease wall tension

Elastic recoil contributes to diastolic pressure that maintains blood flow during diastole

Vessels that develop stiffness due to vascular damage and aging receive the stroke volume and develop elevated systolic pressure, but have decreased recoil, leading to decreased diastolic pressure and flow.

In areas of turbulent flow, such as downstream from an atherosclerotic plaque and in areas of vascular branching, endothelial shear stress is reduced, leading to decreased nitric oxide production. Decreased endothelial nitric oxide production is a hallmark of endothelial dysfunction that contributes to and accompanies atherosclerosis

fatty streak

Endothelial cell injury initiates the process of increased endothelial permeability, soon followed by movement of LDLs into the intima

Upregulation of endothelial adhesion molecules recruits monocytes to the intima, where they differentiate into macrophages and they begin to phagocytose LDLs.

T lymphocytes, dendritic cells, platelets, and mast cells supports plaque growth of the area with cholesterol accumulation continuing to swell the evolving lesion

VSM cells invade the intima and become activated to proliferate and produce extracellular matrix, increasing the intima-media thickness (IMT).

VSM cells produce fibrous cap over the plaque, beneath which inflammatory interactions and cholesterol deposition continues.

as endothelial damage occurs, LDL molecules enter the vascular wall and become trapped there by interacting with the extracellular matrix of the intima.

As in acute inflammation, monocyte attachment to damaged endothelium is followed by movement, in this case to the intima, and differentiation into macrophages. Macrophages begin to ingest (phagocytose) LDL molecules. ROS are generated, causing LDL oxidation. As macrophages detect oxidized LDL, they begin to express scavenger receptors that increase phagocytosis of LDL. As they accumulate cholesterol, macrophages turn into foam cells and can no longer leave the now growing atherosclerotic plaque. Macrophages secrete cytokines that recruit T lymphocytes (T cells) to the plaque. T cells further perpetuate the inflammatory process

autosomal dominant disorder that is associated with lifelong elevated levels of LDL cholesterol

a defect in the LDL receptor that reduces its ability to bind circulating LDL particles and to remove them into cells by receptor-mediated endocytosis

intermittent claudication—pain, ache, cramp, or fatigue of muscles that occurs during exercise and is relieved by rest. Intermittent claudication always presents below the site of stenosis. Physical examination typically finds diminished pulses below the stenosis. The ankle-brachial index (ABI) is based on bilateral measurements of systolic blood pressure made while the person is in the supine position.

a disorder caused by stenosis or occlusion of the aorta or arteries of the limbs

is primarily determined by two factors: cardiac output and peripheral resistance.

neural (baroreceptor reflex by the autonomic nervous system), humoral (circulating mediators such as angiotensin II and vasopressin), and local mediators such as nitric oxide, bradykinin, endothelin, and prostaglandins.

endocrine and include hormones that affect fluid balance, such as aldosterone (secreted by the adrenal cortex), vasopressin (secreted by the posterior pituitary), and natriuretic peptides (secreted by the heart). alter blood volume by modulating fluid output (renal sodium and water excretion) as well as fluid intake (via the hypothalamic sodium and water appetite).

Arterioles represent the primary site of vascular resistance maintaining normal blood pressure. Their radius is directly regulated by intrinsic mechanisms, including action potential activity that opens voltage-gated calcium channels. Extrinsic regulation is by neural and humoral vasoconstrictor and vasodilator substances. Many antihypertensive drugs work by altering cellular mechanisms of contraction and relaxation of VSM.

Veins and venules can alter cardiac output and blood pressure by regulating venous return (amount of blood returned to the right atrium). Normally, veins and venules store a substantial portion of blood volume (capacitance function). During times of hypotension and hypovolemia, the sympathetic nervous system stimulates venoconstriction, increasing venous return (preload) and restoring cardiac output.

Cardiac output = heart rate × stroke volume, so increasing heart rate or stroke volume, or both, will increase cardiac output and thus blood pressure

Blood volume is primarily regulated by the kidneys which conserve sodium (regulated by aldosterone and natriuretic peptides) and water (regulated by vasopressin, also known as antidiuretic hormone).

intrinsic to the VSM cells are involved in ongoing vasoconstriction. For example, membrane voltage-gated calcium channels are one source of calcium entry to support contraction. As electrically excitable cells, smooth muscle cells can have action potentials that open these voltage-gated calcium channels and cause contraction.

Decreased arterial pressure results in decreased stretch
This decreases the firing rate of the carotid sinus nerve
Information is carried to the vasomotor center in the brainstem
The vasomotor center decreases vagal stimulation and increases sympathetic outflow
This will: increase heart rate, increase contractility and stroke volume, and vasoconstrict the arterioles and veins (this increases venous return and increases cardiac output)

Direct stimulation of VSM contraction, increasing peripheral resistance

Increasing body sodium and water content through actions on the kidneys and other tissues

anaphylactic shock [severe type 1 hypersensitivity], septic shock, and neurogenic shock, among other forms

complete cessation of firing of vasoconstrictor sympathetic neurons

Heart attacks can dramatically reduce cardiac output, resulting in cardiogenic shock. The sympathetic nervous system and RAAS respond to increase heart rate and promote vasoconstriction. Because reduced cardiac contractility is the initiating event, CVP becomes elevated but cardiac output remains low. Cardiac output cannot be improved by volume expansion, which can promote pulmonary edema. The focus for treating cardiogenic shock is to restore cardiac contractility as quickly as possible

severe restrictive pericarditis and pericardial tamponade that restrict cardiac filling. Impairment of lung blood flow can also produce obstructive shock, as caused by pulmonary emboli or tension pneumothorax.

in capillaries

intravsascular pressure, radius, and wall thickness

older men, smoking, and family history

increases systolic blood pressure, reduces diastolic blood pressure and flow

shear stress caused by blood flow alongside hydrostatic pressure

abdominal aorta
coronary arteries
thoracic aorta
femoral and popliteal arteries
carotid arteries
vertebral arteries

regions of vascular branching disrupt laminar flow

endothelial injury increases endothelial permeability

LDL cholesterol particles enter the intima from the blood- more LDL more risk

monocytes come, then differentiate to macrophages

macrophages increase cytokine production, enhancing chemotaxis

Macrophages contribute to LDL oxidation/ phagocytosis

Lipid laden macrophages become immobile foam cells

macrophage cytokines recruit new cells to the growin lesion

T lymphocytes, mast cells, platelets, dendritic cells swell the inflammatory lesion

•Initial growth swells vascular external diameter without appreciably narrowing the lumen

in those less than 24 years old

aerobic exercise

cardiac output:
The amount of blood the heart pumps through the circulatory system in a minute

ejection fraction: how much blood leaves the ventricle with each contract 50-75%

high-pressure stretch detectors in carotid sinus and aortic arch

-sensory fibers relaying to medullary nucleus of the solitary tract

multisynaptic pathways control autonomic responses:
•Vagus nerve to heart—parasympathetic slowing when BP goes up
•Sympathetic nerves to heart—increase heart rate when BP goes down
•Sympathetic vasoconstrictor nerves
•Increase firing when BP goes down
•Decrease firing when BP goes up

The reduction in blood volume during acute blood loss causes a fall in central venous pressure and cardiac filling. This leads to reduced cardiac output and arterial pressure

• (warm shock)
-Acute reduction in blood pressure triggers

•an immediate baroreflex -mediated increase heart rate (withdrawal of parasympathetic stimulation)

•SNS mediated increases in HR, contractility, and vasoconstriction

•RAAS activated

•Diminished blood to periphery - CO2 & lactic acid levels rise triggers chemoreceptors in aortic & carotid bodies

increase in sympathetic discharge

tachycardic, peripheral pulses weak/thready, & cool, pale skin

•Transitional phase - development of tissue injury.

•Red blood cells aggregate and stack blocking capillaries further decreasing oxygen & nutrient delivery to tissue

•Ischemic tissues release cytokine and damage signals because of disrupted cellular ATP

•Anaerobic metabolism resulting in widespread lactic acidosis.

•If bodies pH drops severely α- adrenergic receptors become unresponsive to sympathetic stimulation loss of sympathetic tone & circulatory collapse.

(cold shock- beginning of tissue injury)

initially tachycardic, BP severely low; pale or mottled, cool, diaphoretic skin, peripheral pulses weak or absent, changes to level of consciousness.

irreversible changes; shock is unresponsive to treatment

Patient - unresponsive, blood settles and pools in the lowest regions - broad red and purple patches may be evident.

hypovolemic shock

vasoconstriction

decreased preload, decreased cardiac output, increased total peripheral resistance

•Anaphylactic shock—worse case allergic response with generalized histamine release, combined with hypoxia due to airway swelling and obstruction (IgE)

•Septic shock—(warm shock- BOUNDING PERIPHERAL PULSES) generalized infection, inflammatory mediator release [fluid gets third-spaced]

•Neurogenic shock—as in spinal cord injury with loss of medullary projections to spinal sympathetic neurons, loss of tonic vasoconstriction

•Initial state of normal cardiac output, but massive vasodilation with loss of vascular resistance ➡ hypotension

widespread release of histamine is responsible for vasodilatation. Initial hemodynamic changes include decreased TPR, blood pooling in the periphery, decreased venous return, decreased preload and decreased Cardiac output.

caused by IgE

overwhelming systemic infection. It occurs in both children and adult, with increased risk seen in compromised cardiac, lung, or kidney disease. Multiple organ dysfunction syndrome (MODS) is the final stage and represents failure of several organs concurrent with death peripheral tissues. Sepsis morbidity and mortality rates are high and remain among the most challenging of diease syndrome to manage.

Initial hemodynamic changes include decreased TPR, blood pooling in the periphery, decreased venous return, decreased preload and decreased Cardiac output. bounding peripheral pulses

(spinal cord injury or drug overdose). Loss of TPR, blood pooling in periphery, lack of cardiac compensation , decreased CO. Results when there is complete cessation of firing of vasoconstrictor sympathetic neurons. Spinal cord injuries, drug overdoses, and complications from spinal anesthesia all have the potential to interrupt the spinal sympathetic outflow.

due to loss of sympathetic tone- unopposed parasympathetic reaction [vasodilation of lower extremities]; lower legs will be warm and pink- above level will be cold pale mottled

"pump" is broken: decreased cardiac output and increased TPR

•Severe MI produces acute heart failure—failure of ejection
•Rapid decrease in cardiac output—insufficient to support life
•Compensation by vasoconstriction is inadequate to restore BP
•Manage with inotropes, mechanical support devices; volume expansion does not usually help, will fluid overload patient

The SNS and RAAS responded to increased heart rate and promote vasoconstriction. Because reduced cardiac contractility is the initiating event, CVP becomes elevated but CO remains low. Volume expansion will not address hypotension instead it may result in pulmonary edema.

"pump" is failed
Interference with the blood flowing through the cardiovascular system, commonly caused by tension pneumothorax, cardiac tamponade, or pulmonary embolism.

•Pathological blockage of blood flow—severe enough to reduce cardiac output below critical level

•Pulmonary emboli
•Tension pneumothorax - lung collapses, but enough pressure compresses great vessels and heart;
•Pericardial tamponade - adds compression to heart
•Restrictive pericarditis - adds compression to heart

Low cardiac output with elevated TPR

small size and membrane flexibility to easily flow through small capillaries

They bind to plasma transferrin and are transported to the bone marrow for new RBC production

sickle cell trait

sickle cell disease

promoting attachment of adjacent HbS molecules- will stick

What is the heterozygotes version of the mutation of the Hb b chain gene can produce hemoglobin s (HbS)

What is the heterozygotes version of the mutation of the Hb b chain gene can produce hemoglobin s (HbS)

RBCs are microcytic and hypochromic due to reduced hemoglobin concentration
Excess concentration of the unaffected chains (a or b) can cause intracellular protein precipitation and abnormal RBC function

Thalassemia can alter RBC function through the reduced production of the specific globin chains and buildup of abnormal levels of the unaffected globin chains, some of which form cellular precipitates that lead to hemolysis.

iron

plasma iron binding protein, transports iron from gut or spleen to bone marrow for use in new RBC synthesis

Splenic macrophages break down aging red blood cells, releasing 95% of the iron needed for red blood cell synthesis. The iron is released from the spleen and then binds to the plasma carrier protein transferrin for transport to the bone marrow. GI absorption of dietary iron involves a DMT-1 on the apical side of the epithelial cell. Some iron is stored in ferritin in gut epithelial cells (enterocytes), and the remainder leaves the cell by the basolateral ferroportin transporter. Iron then binds to circulating transferrin for transport to the bone marrow.
DMT-1, divalent ion membrane transporter; GI, gastrointestinal; sat, saturated; unsat, unsaturated.

spleens also removes toxins and bacteria

Mean cell volume (MCV): Decreased, microcytosis
Small, pale cells (hypochromic)
Transferrin: Increased
Transferrin saturation: decreased (<20%)
Ferritin: Decreased
Serum iron: Decreased

nucleotide synthesis

needed for DNA replication during proliferation of RBC precursors
Deficiency of either nutrient can cause anemia

Pernicious anemia causes autoimmune destruction of gastric parietal cells with a resulting lack of intrinsic factor prevents vitamin B 12 absorption.
May also occur in patients with chronic gastritis due to H. Pylori infection; malabsorptive conditions such as Crohn disease reduce ileal surface area with the resulting loss of vitamin B12 absorption; parasitic infections of the small intestine as well as certain medications (including metformin and cholestyramine..

Extravascular—abnormal RBCs are rapidly destroyed by the spleen (e.g., sickle cell disease, hereditary spherocytosis, G6PD deficiency)

Intravascular:
Microangiopathic hemolytic anemia—when small blood vessels are blocked by clots that lyse RBCs, for example, HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, thrombotic thrombocytopenia, hemolytic uremic syndrome
Autoimmune and drug-mediated—when RBCs are targeted by antibodies and complement proteins

cell loses its shape

shortage of red blood cells, yellowing of eyes and skin, and enlarged spleen

treatment and complications: transfusions, folic acid administration, full or partial splenectomy, and/or cholecystectomy. Complications of spherocytosis may include megaloblastic crisis, low folic acid levels, splenomegaly, and/or gallbladder problems.

a variant of preeclampsia
H (hemolysis, which is the breaking down of red blood cells)
EL (elevated liver enzymes)
LP (low platelet count)

Occurs later in childbirth or immediately after

treatment:
blood transfusion
get the baby out
magnesium sulfate to reduce seizures

-Genetic disorder, X chromosome [X linked inheritance] mostly in men. G6PD enzyme has abnormal amount or function, RBCs have inadequate protection from oxidative stress

-Exacerbated by oxidizing drugs and some foods (fava beans) antimalarial drugs, sulfonamides, and nitrofurantoin.

-Acute exposure damages RBC integrity—hemolysis increases

-After exposure ends, hemolysis resolves

AIHA classified by the optimal temperature at which antibodies bind the RBC causing lysis.
Warm (80%) of cases and is immunoglobulin G (IgG) mediated. This results in extravascular hemolysis in the spleen or liver.

Cold agglutinin disease results from finding of IgM or complement.

Rapid vasoconstriction when blood vessel is injured
Platelets adhere, are activated, aggregate—primary platelet plug
Coagulation proteins are activated sequentially on platelet surfaces
Fibrinogen is cleaved, fibrin strands bind to platelets, stabilizing clot
Clot retracts after tissue healing is completed

Extrinsic pathway is activated by frank trauma, starts with tissue factor and factor VII

Intrinsic pathway is activated by blood stasis, starts with factor XII—reinforces extrinsic pathway at factor IX step

Healthy endothelium expresses many molecules that inhibit platelets and clotting cascade proteins
Plasmin system lyses clots once tissue has healed
Tissue factor pathway inhibitor blocks extrinsic pathway activity
Clotting cascade proteases are inactivated by antithrombin
Clotting cascade cofactors (V, VIII) are inhibited by the Protein C/Protein S system

Endothelium expresses anti-clotting products:
Nitric oxide—inhibits platelet aggregation, vasodilator
Prostacyclin—inhibits platelet aggregation, vasodilator
Proteoglycan—binds antithrombin III (protease inhibitor)
Thrombomodulin—activates protein C
Tissue factor pathway inhibitor
Intact endothelium covers subendothelial collagen

Endothelial injury
Venous stasis
Hypercoagulability

conditions favorin pathological clot

prone to endothelial injury and atherosclerosis

-Regions of atherosclerotic plaque sustain endothelial damage and activation, losing anti-clotting properties

-Plaque rupture exposes thrombogenic plaque core, rapid thrombus formation results

Large veins have slow flow, low pressure

Blood stasis promotes thrombus formation

Embolization—clot breaks off and ultimately travels to lungs creating pulmonary embol

chronic inflammation: metabolic syndrome and rheumatoid arthritis

acute inflammatory conditions: influenza or pna

other conditions: pregnancy, oral contraceptives, cancer

Protein C doesn't recognize and can't break down Factor 5, making it resistant to cleavage by activated protein C-->more clots either venous thromboembolism or pulmonary embolism

condition associated with autoantibodies [primarily IgG]) directed against protein-binding phospholipids that results in increased coagulation activity.

150000-450000

Most common clinical manifestation = bleeding gums and epistaxis (60%); menorrhagia, hematomas from mild to moderate trauma, excessive post partum bleeding .

Factor VIII deficiency, 4X more common than hemophilia B (Factor IX deficiency)

X-linked inheritance (carrier mother can have an affected son or carrier daughter, affected father can have carrier daughter) - it is possible for an affected daughter if carrier mom + affected father [both X chromosomes are affected or one is affected and the other is missing or non-functioning.]

30% of cases are spontaneous mutations—no prior family history

ab testing—factor levels, activated partial thromboplastin time (aPTT) prolongation

Management
Factor replacement
Therapies in development
Factor VIII analogues
Tissue factor pathway inhibitors
Gene therapy

liver

Liver synthesizes and secretes most of the coagulation (fibrinogen, factor II, V, VII, VIII, IX, X, IX, X, XII, XIII) and anti coagulation (protein c, protein S and AT III) factors.

Deficiencies of bile salt production impair gut absorption of vita soluble vitamins, including Vit K which worsens bleeding tendencies.

>50 % of patients with cirrhosis have thrombocytopenia with a platelet count less than 150,000 because of the lack of liver thrombopoietin production. Additionally patients with portal hypertension develop splenomegaly which accelerates platelet destruction by splenic macrophages.

at 60 days, stimulates erthropoiesis

decreased life span of RBCs lead to Immature liver cannot conjugate bilirubin

or Hemolysis due to ABO or Rh incompatibility with mother—pathological hyperbilirubinemia results from accelerated RBC destruction

Gingival bleeding, excessive bleeding as teeth are lost
Epistaxis is common
May be suspected if neonatal circumcision results in excessive bleeding
Excessive bleedingruising after childhood falls raise concerns of physical abuse, require workup
Contraindication for use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs)

Increased incidence of anemia
Decreased bone marrow cell numbers
Hypercoagulability
Medication-related changes in function
Nutritional deficiencies: Iron > B12 or folate
Anemia of chronic inflammation/chronic disease
Anemia of unknown origin - mechanism not definitively identified at present

Hypercoagulation Factors
Decreased prostacyclin production and second messenger signaling
Increased vWF synthesis

Hypocoagulation Factors
Decreased Platelet Number and Function
Increased use of anticoagulant medications—aspirin, others

Erythropoietin is a glycoprotein synthesized and secreted by the kidneys into the bloodstream that circulates to the bone marrow

erythropoietin stimulates erythropoiesis

tissue hypoxia, hemorrhage, CLS, or high-altitude environments

The transferrin-iron complex carries iron to the bone marrow, where it binds to transferrin receptors on erythroblasts. After the complex has moved into the erythroblast, iron is dissociated from transferrin, and transferrin is returned to the plasma for reuse.

Splenic macrophages break down aging red blood cells, releasing 95% of the iron needed for red blood cell synthesis. The iron is released from the spleen and then binds to the plasma carrier protein transferrin for transport to the bone marrow. GI absorption of dietary iron involves a DMT-1 on the apical side of the epithelial cell. Some iron is stored in ferritin in gut epithelial cells (enterocytes), and the remainder leaves the cell by the basolateral ferroportin transporter. Iron then binds to circulating transferrin for transport to the bone marrow.

meat, eggs, milk, and animal products

including fatigue, generalized weakness, dyspnea on exertion, orthostatic lightheadedness, restless legs syndrome, and tachycardia. Signs of GI bleeding may be present, ranging from melena to stools containing bright red blood.

Anemia of long duration can be associated with pica and the appearance of a smooth tongue and brittle nails. In middle-aged women, iron-deficiency anemia may present with dysphagia due to esophageal webbing, also known as Plummer-Vinson syndrome.

decreased red cell count, hemoglobin, and hematocrit; decreased serum iron and ferritin; increased total iron-binding capacity and transferrin levels; low transferrin saturation; and microcytic, hypochromic RBCs. MCV will be below the normal range (<80 fL). The bone marrow biopsy is the gold standard to confirm the diagnosis

Autoimmune destruction of parietal cells in the stomach, leading to loss of intrinsic factor and thus inability to take up vitamin B12

demyelination can accompany vitamin B12 deficiency anemia. In severe and prolonged cases, demyelination of the posterior columns, lateral corticospinal tracts, and spinocerebellar tracts may occur. This leads to a loss of position and vibratory sensation (particularly in the lower extremities), ataxia, and upper motor neuron signs, such as increased deep tendon reflexes, spasticity, weakness, and an extensor Babinski sign. Sensory paresthesias may also be present.

secondary to infections: subacute bacterial endocarditis, ostemolyelitis, pyelonephritis, or late stage HIV

malignancies:
tumors

connective tissue diseases lasting at least 1 month: rheumatoid arthritis, systemic lupus erythematosus (SLE), and polymyalgia rheumatica.

Intravascular hemolysis occurs within the blood vessels, and extravascular hemolysis occurs within the reticuloendothelial system, primarily the spleen.

Intravascular hemolysis can occur secondary to clotting disorders that block small blood vessels, termed microangiopathic hemolytic anemia, as seen in thrombotic thrombocytopenia purpura, hemolytic uremic syndrome, or HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome of pregnancy.

increased rate of RBC breakdown

X-linked inheritance pattern- stimuli that precipitates oxidative stress will exhaust RBC supply

med/food that will precipitate oxidative stress:
several antimalarial drugs, sulfonamides, and the antibiotic nitrofurantoin. Dietary oxidants can also precipitate hemolysis, in particular, ingestion of fava beans. A

Aspirin is an irreversible inhibitor of COX-1 to entire life span of platelet.

Platelet cyclooxygenase-1 (COX-1) is stimulated by platelet activation, and begins to produce TXA2, which further stimulates platelet function and vasoconstriction.

In primary hemostasis, vessel constriction (due to endothelin released by endothelial cells and serotonin from platelets) is rapidly followed by platelet adhesion and aggregation to form a platelet plug.

In secondary hemostasis, zymogens (protease enzymes in their precursor and active forms) and cofactors undergo a series of activations leading to a stable clot made out of fibrin deposited on and within the platelet plug.

Thrombin cleaves the large, soluble plasma protein fibrinogen, releasing small, sticky fibrin monomers that attach to the platelet surface and are cross-linked, forming a tightening web of fibrin strands in and around the platelet plug.

on the membrane of activated platelets, where zymogens and cofactors are stabilized on the phospholipid surface by calcium ion binding

tissue damage
Factor VIIa initiates the common pathway, generating factor Xa, which, stabilized by factor Va, functions as prothrombin convertase, cleaving prothrombin to release active thrombin.

Factor VIIa also activates factor IX, adding intrinsic pathway reinforcement of the early extrinsic pathway activity.

Thrombin binds to receptors on platelets, contributing to rapid platelet activation.

Thrombin cleavage of fibrinogen begins to generate fibrin monomers in and around the platelet plug.

Thrombin cleaves and activates cofactors V and VIII, increasing the local concentration of activated cofactors

Thrombin cleaves and activates factor XI, leading to accelerated activation of factor IX. Factors IXa and VIIIa bind to the platelet surface to increase the rate of factor X activation. As a result, much of factor X activation during a prolonged injury-induced clotting event results from the factor IX pathway.

activation of factor XIII, the agent that cross-links fibrin strands to tighten the clot.

factor XII

factor XII cleaves and activates factor XI and high-molecular-weight kininogen.

Endothelial cells constitutively express nitric oxide synthase (NOS) and release nitric oxide (NO), a potent inhibitor of platelet activation and aggregation.

Endothelial cells also tonically metabolize arachidonic acid to prostacyclin, a potent local inhibitor of platelet activation and aggregation.

Endothelial cell membranes express the enzyme adenosine diphosphatase (ADPase), which breaks down adenosine diphosphate (ADP) released from granules of activated platelets.

Fibrinolysis is triggered by tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), enzymes that convert the precursor plasminogen into plasmin. Plasmin degrades fibrin clots and releases fibrin degeneration products that are unable to polymerize

circulating activated clotting factors are taken up by the liver and are degraded

antithrombin inactivates major coagulation proteases: XII, XI, IX, VII, X, II.

Antithrombin is potentiated by bound to exogenous heparin from endothelial cells.

protein C/protein S cleaves and inactivates factors VIII and V. protein C binds to endothelial thrombomodulin and this binds to thrombin

The plasmin system is responsible for breaking down clots when healing has occurred. tPA and uPA cleave the protein plasminogen in the circulation and bound in the clot to release plasmin. Plasmin is an enzyme that breaks down cross-linked fibrin within the clot, dissolving the clot and releasing fibrin breakdown products such as d-dimer.

1. Venous stasis
2. Hypercoagulability
3. Trauma to a vessel

major factors that contribute to abnormal blood clotting in the absence of frank vascular breaks

endothelial injury is most characteristic of thrombi that form in arteries

blood stasis is most characteristic of thrombi that form in veins, particularly those draining the legs, and in the atria of patients with atrial fibrillation.

Mutated form of factor V that lacks cleavage site for deactivation by proteins C and S

leads to hypercoagubility and increased risk of thromboembolic events

Autoimmune syndrome characterized by autoantibodies against plasma membrane phospholipids and phospholipid-binding proteins.

results in increased clotting

more susceptible in patients with recurrent thromboembolic events and in women with repeated pregnancy losses or complications

mucosal bleeding
report hematomas following mild to moderate trauma, menorrhagia, excessive postpartum bleeding, gingival bleeding, and occasional GI bleeding

Deficiency or defective von Willebrand's factor (vWF) w/ low levels of Factor VIII

DDAVP, which is a synthetic antidiuretic hormone that works on type 2 vasopressin receptors to increase secretion of vWF and factor VIII

high risk of joint-related hemarthroses, spontaneous hematuria, mucous membrane bleeding, and hematoma formation that are managed with clotting factor replacement.

i. DNA polymerases are responsible for the process of DNA repair during replication. Enzymes identify errors in the sequences and removes the incorrect nucleotide and replaces it with a correct one

Normally spontaneous or consequence of chemical or radiation induced injury;

1. Reactive oxygen species
2. Chemical mutations from environmental or occupational exposures
3. Radiation [sun exposure]
4. Failure of cellular protective strategies

1. Silent: change in genotype dose not change phenotype
2. Missense: altering a nucleotide changes one amino acid in the protein product
3. Nonsense: altering a nucleotide inserts a premature stop codon, protein is truncated and nonfunctional

1. Insertion [addition of base pairs] mutations alters reading frame and amino acid sequence

2. Deletion [deletion of base pairs] mutation alters reading frame and amino acid sequence

serum phenylalanine at 3 days old

● early intervention with a diet limited in phenylalanine can avoid most of the serious consequences of PKU, so early detection is critical→ autosomal recessive

i. autosomal dominant: mutation of the FBNI
1. Tall stature, aortic dilation and dissection, scoliosis, joint hypermobility, arachnodactyly, pectus excavatum, and mitral valve proplapse

50% chance of male or female child being affected

i. all female children are affected; no male children affected

50% chance of female child being carrier, 50% chance of male being affected

i. all female children are carriers, all male not affected

A genetic predisposition (sometimes also called genetic susceptibility) is an increased likelihood of developing a particular disease based on a person's genetic makeup. A genetic predisposition results from specific genetic variations that are often inherited from a parent.

● CAD is a progressive disorder resulting from the accumulation of atherosclerotic plaque in the coronary arteries and associated inflammation
○ multigenic/multifactoral disease
○ Family hx considered in risk calculations
○ Certain rare, single fene disorders increase risk and earlier onset
● Familiar hypercholesterolemia
● Familial defective apolipoprotein A
○ Relevant gene mutations:
● SLC01B1- increased myopathy risk from statins
● CYP2C19- prevent hepatic activation of clopidogrel

Residing in the nucleus, DNA must be replicated to create an identical copy before cells can undergo mitosis, producing identical daughter cells.
● Very stable; double helix; connected by hydrogen bonds between base pairs
● Backbone = deoxyribose sugars connected by phosphate bonds (polarity based on the free ends of the chain)
● DNA bases and base pairs
○ Adenine and thymine (two hydrogen bonds)
Guanine and cytosine (three hydrogen bonds

- If one parent has the disorder, there is a 50% chance he/she will pass on the abnormal copy of the gene to each offspring
- Sexes are equally likely to be affected/transmit the gene
- Affected person will have at least one affected parent
Diseases:
- Huntington
- Familial hypercholesterolemia
- Marfan syndrome
Neurofibromatosis

- If one parent is a carrier and the other is not affected (doesn't have disorder) and is not a carrier with each pregnancy there is a 50% chance that their offspring will be a carrier
- If both parents are carriers, but neither has the disorder there is a 25% chance the offspring will have the disorder, 50% chance they will be a carrier and 25% chance nonaffected noncarrier
- If affected individual mates with a nonaffected noncarrier, all of the offsprings will be carriers but none will be affected or nonaffected noncarriers
- If an affected individual mates with a carrier, there is a 50% chance their offspring will be affected and 50% chance they'll be a carrier

- Both sexes are equally affected

- Cystic fibrosis
- PKU
- Sickle Cell anemia
Tay sachs disease

- Rett syndrome
- Fragile X syndrome
X-linked hypophosphatemia

General term describing any chromosomal number other than the normal set of 46 chromosomes

○ Coarctation of the aorta
○ Scolosis
○ Hypothyroidism
■ The thyroid gland becomes under-active in about 10 percent of women
○ Diabetes (type II)
○ Osteoporosis

affects women- only has one X chromosome

● Small stature (shorter than average) with no growth spurt at puberty
● Poorly developed secondary sex characteristics
● Ovarian dysgenesis (no period or breast development without hormone therapy. Vagina and womb are totally normal though)
● Retardation of bone age (scoliosis, osteoporosis due to lack of estrogen)
● Webbed neck
● recurrent/frqeuent middle ear infection→ r/f hearing loss
● Good reading/verbal, poor math/memory/fine finger movement
● Lower or indistinct hair line
● Broad chest/widely spaced nipples
● Arms that turn out slightly at the elbow
● Heart murmur due to narrowing of aorta
● High blood pressure
● Minor eye problems (corrected with glasses)

● Epicanthal folds, slanted eyes, flat facial profile, simian crease in hands
● Growth failure
● Cognitive delay
● Congenital heart disease
● Malformed ears
● Big/protruding tongue
● Intestinal malformation
● Shortroad hands
● Wide gap between 1st and 2nd toe

● Aganglionic megacolon
● Acute lymphoblastic leukemia
● Early-onset Alzheimers

● Are developed from multipotent stem cells. It is stimulated by erythropoietin, stem cell factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin 3 (IL-3), BFR-Es proliferate into about 1,000 daughter cells that mature into colony-forming units-erythrocytosis (CFU-Es). Requires the proper cytokines, and availability of folate and vitamin B12.
● Tissue hypoxia (anemia, hemorrhage, chronic lung disease or high altitude ) stimulates increased erythropoietin production.
● Severe hypoxia may increase RBC production up to six time the normal level.
● Patients with chronic kidney disease have reduced erythropoietin production, which can lead to anemia.

100-120 days

● Fetal RBCs have a shorter life span- hemolysis contributes to neonatal jaundice→ 45-70 days
● Birth transition- RBC numbers decline, H and H nadir at 60 days, stimulating erythropoiesis
● Rapid growth contributes to high rates of iron deficiency anemia (breastfeeding is also a factor) and adolescence is also a time of increased anemia (diet change, period)
● Postnatal development of RBC includes: progressive decrease in cell size (MCV), drop in hgb concentration to a minimum between ages 2-6 months, followed by recovery to adult levels
● Older adults: decreased bone marrow cell numbers (fewer stem cells, fatty infiltration decreases functional tissue), thymus (involution- reduced lymphocyte production)

● State of iron imbalance due to chronic cytokine stimulation of the regulatory protein hepcidin
○ Hepcidin inhibits the iron transporter ferroportin—iron cannot leave cells
○ Iron builds up in gut cells and splenic macrophages and cannot reach the bone marrow
○ Findings include microcytic anemia (as in iron deficiency) and low reticulocyte count
○ Ferritin levels are normal, indicating normal total body iron stores

● Platelet glycoproteins allow: binding to von Willebrand factor, binding to fibrinogen, fibrin strands (aggregation)

● G protein-coupled receptors cause activation stimulated by ADP, thromboxane A2, and thrombin

○ Antibodies are produced against the platelet membrane glycoprotein or human leukocyte protein. Antibody binding "targets" the platelets for destruction by macrophages in the spleen and liver. First line therapy = steroids or IV immunoglobulin G (IVIG) infusions

● Most common cause is chronic inflammation: Metabolic syndrome (obesity, hypertension, truncal obesity, dyslipidemia, and insulin resistance ---- results in pro inflammatory markers) and Rheumatoid arthritis
○ Acute inflammatory conditions: influenza or pneumonia
○ Other conditions: Pregnancy, Oral contraceptives/hormone replacement (Estrogens increase liver synthesis of clotting proteins and decrease synthesis of protein S and AT-III (promotes clot formation), Cancer (Tumor cells have innately increased ability to initiate the clotting cascade)

Genetic disorder: Factor 5 Leiden
● Missense mutation- arginine replaced by glutamine
● The mutation alters factor V, making it resistant to cleave by activated protein c
● Significantly increased risk of venous thromboembolism, PE

○ Autoimmune disorder- antiphospholipid syndrome
● Often comorbid with other autoimmune disease (Lupus)
● Lab evaluations document antiphospholipid antibodies and other antibodies- relationship between these antibodies and hypercoagulability is unknown
● Spontaneous abortions in women of reproductive age, associated with preeclampsia and eclampsia
● Stroke and MI n men and women with no RF raises suspicion of this syndrome
● APS patients have elevated levels of antibodies against the phospholipid-binding plasma protein cardiolipin or β-glycoprotein 1 or both in addition to lupus anticoagulant antibodies

○ thrombocytopenia
● Plt # <150,000
● Superficial bleeding of increasing severity- petechiae, purpura, ecchymoses
● Other excess bleeding: gingival, epistaxis, menorrhagia
● Postinfectious: most common in children, spontaneous resolution
Autoimmune: more common in adults, managed with steroids or IV IgG

● results from heparin binding to platelet membranes
■ Immune response initiated- platelets are rapidly destroyed (they get eaten)
■ Resolves when heparin therapy stops- contraindication to future heparin treatment
■ ​​Results from the development of IgG antibodies to the platelet membrane complexes of heparin bound to platelet factor 4. This occurs within 5-10 days of exposure to heparin
■ The antibodies bind to the platelet surface stimulating platelet activation, with this activation there is an abundant release of procoagulants and consumption of platelets leading to thrombocytopenia.
■ Thrombocytopenia increases thrombosis risk. In HIT there is an increased production of thrombin as well as stimulation of inflammatory mediators. This cascade results in endothelial injury and increases the risk of large-vessel arterial or venous thrombosis.
■ Laboratory findings - platelets decreased, hallmark is an immunoassay for the antibodies to the heparin-platelet factor 4 complex or a function study looking at platelet aggregation when exposed to heparin.
■ Lifelong avoidance of all heparin produces.

○ affects platelet adhesion and factor VIII availability
● Genetic disorders- 6 subtypes, type I represent 70% of cases, autosomal dominant with incomplete penetrance
● Mechanism of clotting defect: decreased vWF levels- reduces platelet adherence to damaged endothelium, decreased factor VIII levels- reduces factor IX effectiveness
■ decrease in circulating vWF + decreased Factor VIII levels- increased bleeding time + clot formation is inadequate
● Findings: mucosal bleeding, epistaxis, suspected in excessive childhood bruising, menorrhagia
■ hematomas from mild to moderate trauma, excessive post partum bleeding
● Lab testing: ristocetin test stimulates vWF-platelet binding, agglutination abnormal in those with disease
● Roles - facilitating platelet aggregation at sites of vascular injury and helping to bind factor VIII to the platelet plug. - important step in the production of thrombin, fibrin, and eventual clot formation
● Defect on chromosome 12

Hemophilia A
■ Genetic disorder
■ Factor VIII deficiency, 4X more common than hemophilia B (Factor IX deficiency)
■ X-linked inheritance (carrier mother can have an affected son or carrier daughter, affected father can have carrier daughter)
■ 30% of cases are spontaneous mutations—no prior family history
■ Mechanism of clotting defect
● Factor VIII is required cofactor for factor IX activity
● Lack of factor VIII decreases reinforcing action of factor IX on the extrinsic pathway
● Severe factor deficiency associated with deep bleeds into joints (hemarthroses), hematomas, intracranial bleeds
■ Lab testing—factor levels, activated partial thromboplastin time (aPTT) prolongation
■ Management
● Factor replacement
● Therapies in development
● Factor VIII analogues
● Tissue factor pathway inhibitors
● Gene therapy

○ Endothelial injury
○ Venous stasis
○ Hypercoagulability

● Venous stasis and other states of low blood flow promote pooling of the blood, prolonged contact with endothelium that may reduce some of its anticlotting properties, and activation of the intrinsic clotting pathway
● Immobile during long trips, patients with reduced mobility secondary to an orthopedic procedure or prolonged illness

● Mural thrombi are thrombi that attach to the wall of a blood vessel and cardiac chamber. Mural thrombus occurrence in a normal or minimally atherosclerotic vessel is a rare entity in the absence of a hypercoagulative state or inflammatory, infectious, or familial aortic ailments
● Mural thrombi of the heart most commonly occur from atrial fibrillation, endocarditis, or post-myocardial infarction. Mural thrombi can be treated by acute thrombolysis or by long-term anticoagulation

one way valves

poor circulation, narrowing of vessels

Retinopathy (an eye condition); Nephropathy (a kidney condition); Atherosclerosis (hardening of the arteries); and Coronary/peripheral heart disease

Radiation, Chemicals, Free Radicals, Viruses, Heredity

● Genetic changes in a normally functioning cell that gradually transform the cell into a cancer cell. These result in the inability of body to restrain cell division and can lead to spread of the cancer cells around the body

● Uncontrolled proliferative signaling
● Evading growth suppressors
● Genomic instability
● Enabling cell immortality
● Resisting cell death
● Hijacking or generating blood supply sources for nourishment
● Acquiring invasive and metastatic abilities

○ favorable environment: decline in DNA reapir mechanisms, increased senescent cell number, decreased immune surveillance, longer exposure to environmental and endogenous sources
○ Accumulation of cellular mutations: mutations of DNA sequences in cells that reroute pathways regulating tissue homeostasis, cell survival or cell death. Cells more likely to accumulate mutations to develop one that triggers the development of cancer.
○ Decline in immune function: decline in thymic output of T- cells, decline in t cell and responsiveness contribute to reduced immune surveillance
○ Alterations in hematopoietic stem cells: cascade of changes in homeostasis with aging including a decline in organ function that affects the hematopoietic system, primarily stem cells. Hematopoietic reserves are depleted during aging and their ability to renew deteriorates, ability to differentiate into different cells is altered

● A paraneoplastic syndrome is a set of signs and symptoms that occur in people with a cancerous tumor. They develop when a malignant tumor releases a substance (hormone/protein) which affects a certain body system or when the body's immune system releases a substance (antibody) meant to kill the tumor but also damages healthy body cells (autoimmune response).

● ​​Paraneoplastic syndromes a constellation of clinical findings and effects from a primary malignancy. These syndromes are mediated by hormones secreted by the malignant cells and/or the immune response the hormones trigger.

● Endocrine-secreting tumor cells can induce symptoms of hyperparathyroidism or syndrome of inappropriate antidiuretic hormone (SIADH, look for CA [small cell carcinoma])

● Common is SIADH from tumor-produced vasopressin associated with lung cancers

● Hyper-parathyroid hormone-related protein - causes hypercalcemia and bone loss.

read notes

read notes; occurs due to chronic stress is inflammatory or injurious in nature that results in deregulated proliferation of cells

necrotic: cells swell, rupture, spill signals of tissue danger, initiate inflammation

apoptosis: cells shrink, small blebs containing contents break off, noninflammatory

autophagic: some cells digest their own contents, provide nutrients for other cells in the surrounding region, non inflammatory

Antibiotics kill healthy GI flora which leads to overgrowth of C. difficile bacteria. C. difficile causes pseudomembranous colitis by producing exotoxins which cause mucosal injury, inflammation, and diarrhea.

infection likely due to abx use and proton pump inhibitor use

● Innate immune response
○ Fast acting responding broadly to pathogen features not a specific pathogen.
○ Based on WBC and Scavenger cells that live within the tissues. These cells signal other immune cells with cytokines and chemokines recruiting them to the site of infection. Activated immune cells ingest pathogens
○ Moles of innate immunity include - proteins of the complement cascade - which directly attack and lyse bacterial.
○ These cells interact and communicate with cells involved in adaptive immune response.

○ Slower to respond but highly specific
○ A small number of these cells remain in the body (memory cells)
○ B- lymphocytes
○ Cytotoxic T lymphocytes
○ T-helper lymphocytes (T-helper cells).
○ Adaptive response produces immunological memory - vaccines are based upon this.

transformation of B cells into plasma cells that produce and secrete antibodies to a specific antigen.

Neutralization: Antibodies "neutralize" a pathogen by interfering with its ability to infect host cells. For example, when an antibody binds to the surface of a virus, it may impair the ability of the virus to attach to or gain entry into target cells, effectively inhibiting the infection.

Opsonization: Antibodies function as opsonins, which "tag" pathogens for destruction. Specifically, the formation of the antigen-antibody complex attracts and stimulates phagocytic cells that engulf and destroy the pathogen.

Complement: Antibodies can activate the complement system, which plays a role in both innate and adaptive immunity. The complement system is a sequential cascade of more than 30 proteins. With the help of antibodies, these proteins opsonize pathogens for destruction by macrophages and neutrophils, induce an inflammatory response with the recruitment of additional immune cells, and promote lysis (destruction) of the pathogen.

● IgE—monomer; responsible for allergic responses
● Least abundant(< 1%) IgE binds to mast cells and basophils interacting with its specific Receptor that is present on these innate cells.
● This binding triggers the release of preformed granules containing histamines and inflammatory molecules.
● Useful for eliminating parasites such as helminth worms.
● Very potent and cause tissue damage. It is associated with hypersensitivity type I diseases aka atopic diseases or allergies.

● Mechanisms are still poorly understood
● Genetic vulnerability is indicated by family history
● Tolerance by T cells is assessed during thymic development—potential autoreactive cells are detected and undergo apoptosis
● T regulatory cells can also suppress inappropriate immune responses
● Failure of tolerance leads to autoimmune disease
● Hypothetical mechanisms leading to autoimmunity
● Combination of genetic susceptibility and environmental triggers
● Early events cannot be clinically detected
● Progression to chronic tissue inflammation and fibrotic changes impairs function, causes pain, and target organ dysfunction
● Characteristic autoantibodies can be measured for diagnostic use
● General mechanisms in autoimmunity. The mechanisms underlying predisposition to autoimmune disease are not known, but family history is usually positive for members with one or more types of autoimmune disease. Against this background, it is thought that environmental exposures or prior infections can trigger autoreactivity. Autoantibodies are often present before any overt disease symptoms. Over time, the autoimmune response increases, with tissue damage resulting from immune and complement activation.

small size and membrane flexibility to easily flow through small capillaries

they bind to plasma trensferrin and are transported to the bone marrow for new RBC production

-healthy endothelium expresses many molecules that inhibit platelets and clotting cascade proteins

-plasmin system lyses clots once tissue has healed

-tissue factor pathway inhibitor blocks extrinsic pathway activity

-clotting cascade proteases are inactivated by antithrombin

-clotting cascade cofactors [V, VIII] are inhibited by the protein C/Protein S system

endothelium expresses:

nitric oxide
prostacyclin: inhibits platelet aggregation, vasodilator
proteoglycan: binds antithriombin III
thrombomodulin: activates protein C
tissue factor pathway inhibitor

the plasmin system breaks down clots when healing is occurred. tPa and uPa cleave the protein plasminogen in the circulation and bound in the clot to release plasmin. Plasmin is an enzyme that breaks down cross linked fibrin within the clot. Dissolving the clot and releasing fibrin breakdown products such as D-dimer, tpa, tissue plasminogen activator, uPa, urokinase type plasminogen activator

the circulating mediator AT-III binds to endothelial cell proteoglycans and inactivates proteases. PROTEIN c AND PROTEIN s WORK TOGETHER TO CLEAVE AND INACTIVATE PROTEINS VIII AND V- the required cofactors for factors IX and X

Chronic disease, severe infection, and the use of certain medications can all affect the body's blood-clotting ability

-Deliver blood from the heart to the tissues (conduit vessels)

-Distribute blood flow to the multiple parallel circuits of the systemic circulation

-Maintain blood pressure and blood flow during diastole

Wall tension (T) is increased by both pressure (P) and radius (r), but decreased by wall thickness (h).

the compensatory mechanism for increased vascular pressure is to increase wall thickness in blood vessels (vascular hypertrophy). This increase in wall thickness helps to offset the effect of increased pressure and decrease wall tension

Elastic recoil contributes to diastolic pressure that maintains blood flow during diastole

Vessels that develop stiffness due to vascular damage and aging receive the stroke volume and develop elevated systolic pressure, but have decreased recoil, leading to decreased diastolic pressure and flow.

In areas of turbulent flow, such as downstream from an atherosclerotic plaque and in areas of vascular branching, endothelial shear stress is reduced, leading to decreased nitric oxide production. Decreased endothelial nitric oxide production is a hallmark of endothelial dysfunction that contributes to and accompanies atherosclerosis

fatty streak

Endothelial cell injury initiates the process of increased endothelial permeability, soon followed by movement of LDLs into the intima

Upregulation of endothelial adhesion molecules recruits monocytes to the intima, where they differentiate into macrophages and they begin to phagocytose LDLs.

T lymphocytes, dendritic cells, platelets, and mast cells supports plaque growth of the area with cholesterol accumulation continuing to swell the evolving lesion

VSM cells invade the intima and become activated to proliferate and produce extracellular matrix, increasing the intima-media thickness (IMT).

VSM cells produce fibrous cap over the plaque, beneath which inflammatory interactions and cholesterol deposition continues.

as endothelial damage occurs, LDL molecules enter the vascular wall and become trapped there by interacting with the extracellular matrix of the intima.

As in acute inflammation, monocyte attachment to damaged endothelium is followed by movement, in this case to the intima, and differentiation into macrophages. Macrophages begin to ingest (phagocytose) LDL molecules. ROS are generated, causing LDL oxidation. As macrophages detect oxidized LDL, they begin to express scavenger receptors that increase phagocytosis of LDL. As they accumulate cholesterol, macrophages turn into foam cells and can no longer leave the now growing atherosclerotic plaque. Macrophages secrete cytokines that recruit T lymphocytes (T cells) to the plaque. T cells further perpetuate the inflammatory process

autosomal dominant disorder that is associated with lifelong elevated levels of LDL cholesterol

a defect in the LDL receptor that reduces its ability to bind circulating LDL particles and to remove them into cells by receptor-mediated endocytosis

intermittent claudication—pain, ache, cramp, or fatigue of muscles that occurs during exercise and is relieved by rest. Intermittent claudication always presents below the site of stenosis. Physical examination typically finds diminished pulses below the stenosis. The ankle-brachial index (ABI) is based on bilateral measurements of systolic blood pressure made while the person is in the supine position.

a disorder caused by stenosis or occlusion of the aorta or arteries of the limbs

is primarily determined by two factors: cardiac output and peripheral resistance.

neural (baroreceptor reflex by the autonomic nervous system), humoral (circulating mediators such as angiotensin II and vasopressin), and local mediators such as nitric oxide, bradykinin, endothelin, and prostaglandins.

endocrine and include hormones that affect fluid balance, such as aldosterone (secreted by the adrenal cortex), vasopressin (secreted by the posterior pituitary), and natriuretic peptides (secreted by the heart). alter blood volume by modulating fluid output (renal sodium and water excretion) as well as fluid intake (via the hypothalamic sodium and water appetite).

Arterioles represent the primary site of vascular resistance maintaining normal blood pressure. Their radius is directly regulated by intrinsic mechanisms, including action potential activity that opens voltage-gated calcium channels. Extrinsic regulation is by neural and humoral vasoconstrictor and vasodilator substances. Many antihypertensive drugs work by altering cellular mechanisms of contraction and relaxation of VSM.

Veins and venules can alter cardiac output and blood pressure by regulating venous return (amount of blood returned to the right atrium). Normally, veins and venules store a substantial portion of blood volume (capacitance function). During times of hypotension and hypovolemia, the sympathetic nervous system stimulates venoconstriction, increasing venous return (preload) and restoring cardiac output.

Cardiac output = heart rate × stroke volume, so increasing heart rate or stroke volume, or both, will increase cardiac output and thus blood pressure

Blood volume is primarily regulated by the kidneys which conserve sodium (regulated by aldosterone and natriuretic peptides) and water (regulated by vasopressin, also known as antidiuretic hormone).

intrinsic to the VSM cells are involved in ongoing vasoconstriction. For example, membrane voltage-gated calcium channels are one source of calcium entry to support contraction. As electrically excitable cells, smooth muscle cells can have action potentials that open these voltage-gated calcium channels and cause contraction.

Decreased arterial pressure results in decreased stretch
This decreases the firing rate of the carotid sinus nerve
Information is carried to the vasomotor center in the brainstem
The vasomotor center decreases vagal stimulation and increases sympathetic outflow
This will: increase heart rate, increase contractility and stroke volume, and vasoconstrict the arterioles and veins (this increases venous return and increases cardiac output)

Direct stimulation of VSM contraction, increasing peripheral resistance

Increasing body sodium and water content through actions on the kidneys and other tissues

anaphylactic shock [severe type 1 hypersensitivity], septic shock, and neurogenic shock, among other forms

complete cessation of firing of vasoconstrictor sympathetic neurons

Heart attacks can dramatically reduce cardiac output, resulting in cardiogenic shock. The sympathetic nervous system and RAAS respond to increase heart rate and promote vasoconstriction. Because reduced cardiac contractility is the initiating event, CVP becomes elevated but cardiac output remains low. Cardiac output cannot be improved by volume expansion, which can promote pulmonary edema. The focus for treating cardiogenic shock is to restore cardiac contractility as quickly as possible

severe restrictive pericarditis and pericardial tamponade that restrict cardiac filling. Impairment of lung blood flow can also produce obstructive shock, as caused by pulmonary emboli or tension pneumothorax.