BLOCK 4 - Chapter 36, 20-24 (Dr. Chade)

***STEPS OF PLATELET PLUG

1. ADHESION 2. ACTIVATION 3. AGGREGATION 4. COAGULANT ACTIVITY

*****Whenever a blood vessel is severed or ruptured, hemostasis is achieved by:

1.Vascular Spasm (contraction) 2.Platelet plug 3.Formation of clot (due to coagulation) 4.Clot Retraction (growth of fibrous tissue)

***What causes low CO / what are some examples?

A.Cardiac factors: coronary artery blockage, valvular disease, myocarditis, cardiac tamponade, cardiac metabolic derangements B.Decreased venous return: decreased blood volume (hemorrhage), venous dilation (SN deactivation), large vein obstruction, decreased tissue mass.

Why is the blood flow to muscle during exercise rhythmic?

Rhythmical contraction of skeletal muscle causes rhythmical flow----vessels are compressed during contraction (less flow).

RIGHT CORONARY ARTERY

Right ventricle and posterior part of left ventricle

****Intrinsic Pathway

SLOWER PATHWAY --- REQUIRES Ca++ similar to extrinsic, but more steps. 3. Activated Factor X -- (prothrombin activator) uses protease and splits pro-thrombin into thrombin (FINAL CLOTTING PROCESS) 4. FACTOR V -- promotes and accelerates thrombin formation (POSITIVE FEEDBACK)

**QUESTION: where are the COAGULATION FACTORS found and how are they activated?

They are found circulating in the tissues. They are activated when the vessels are ruptured, and it comes in contact with platelets.

**Where are the ACTIVATOR SUBSTANCES found? What are they?

They are found from damaged walls, from platelets, from blood proteins adhering to the traumatized wall to imitate clotting. Activator Substances •Collagen and microfibrillar proteins (vWF) •ADP released from damaged RBCs activate platelets •Thromboxane from activated platelets •Platelet activating factor from basophils •Epinephrine (stress) •Thrombin

Cardiac Index (CI)

a measure of the cardiac output of a patient per square meter of body surface area. CI = CO/Surface area CI peaks around 10 years old (4 L/min/m2), then gradually declines with age. At 80 years, cardiac index is roughly half its peak at age 10.

*thrombosis

abnormal condition of a blood clot

What is the venous return made out of?

all the local blood flow from tissues summate into the venous return

PLASMIN

an enzyme that dissolves the fibrin of blood clots allows for reversible clotting

cardiac output (CO)

is the quantity of blood pumped into aorta each minute **CO = AP/TPR Values in healthy, young adults: men - 5.6 L/min women - 4.9 L/min

****Venous Return (VR)

is the sum of venous flow from all local tissues into the right atrium. ********Under unstressed conditions, it is the MOST IMPORTANT Determinant of cardiac output.

**Bainbridge reflex

neural reflex activated by stretch receptors in the atria VR increased --> increased atrial filling --> increased atrial stretch --> increase heart rate ****Stretch the heart - makes it pump harder

LEFT CORONARY ARTERY

one of two arteries from the aorta that nourish the heart; (runs from left side of heart then divides into the circumflex and left anterior descending branches) Left coronary artery --IV septum, anterior and lateral portions of left ventricle

Why do veins constrict during exercise?

pushes blood toward heart and increases mean systemic filling pressure. Consequently, increases venous return and CO.

What is the relationship between CO and TPR?

they have opposite relationship when TPR increase (vasoconstriction), CO is decreased CO = AP / TPR Arterial pressure = TPR X CO

What do dormant capillaries do during exercise?

they open to increase nutrient intake

**** additional INTRAVASCULAR ANTICOAGULANTS

****Antithrombin action of FIBRIN (they are formed with formation of clot but act to bind or absorb thrombin) ****Antithrombin III (alpha-globulin, combines with heparin) antithrombin destroys thrombin not bound to fibrin. ****Heparin

***WHAT IS CO DETERMINED BY?

****TISSUE METABOLISM PERIPHERAL FACTORS: VENOUS RETURN FRANK STARLING MECHANISMS

****How does the heart become hypoeffective?

***ANY FACTOR THAT DECREASES THE HEART'S ABILITY TO PUMP BLOOD examples: Coronary artery occlusion/heart attack (AMI) Suppression of sympathetic activity to heart (neural lesion, ganglionic blockade) Cardiac ischemia (angina pectoris) Myocarditis (infection) Pericarditis (constrictive) Valvular disease (congenital) Increased AP ("afterload")

**How can the heart increase the CO to over 25L/min? (more than the heart limit when hypereffective)

***Cardiac hypertrophy + sympathetic stimulation can increase CO up to 40 L/min

Antithrombotic Properties of the Endothelium

***Prevention of blood clotting in the normal vascular system -Smoothness of endothelial cells -Uninjured endothelium does not bind platelets -Layer of glycocalyx—repels clotting factors and platelets -Thrombomodulin—binds and removes thrombin and forms a complex called thrombomodulin-thrombin that... *****Activates protein C—inactivates Factors V and VIII

**What metabolic factors increase blood flow?

***major is the decrease in O2 increased levels of adenosine, CO2, lactic acid, potassium, NO (usually triggered by¯O2)

****COMMON PATHWAY (3 steps)

1. Formation of prothrombin activator in response to blood damage or vessel rupture. Requires the production of PROTHROMBIN ACTIVATOR from the intrinsic and extrinsic pathway. (in presence of Ca++) 2. Conversion of prothrombin into thrombin 3. Conversion of fibrinogen into fibrin threads

***Anti-coagulant - USED CLINICALLY

1. HEPARIN: immediate anticoagulation, effects last up to 4 hours. (Heparinase destroys circulating heparin) Commercial overdose---> stop infusion 3-4 hrs, + protamine to inactivate 2. COUMARINS---competes with Vitamin K, takes ~ 24-48 hours to reach full effect. Coagulation returns to normal within 3 days after stopping treatment. Reverse with FFP (fresh frozen plasma) and Vitamin K

What are the factors that control the flow in the skeletal muscle?

1. Local regulation reduced O2 availability due to rapid consumption → vasodilation triggered by local metabolites (lactic acid, adenosine, K+, CO2) 2. Functional hyperemia: increase in blood flow when muscle is active. 3. Nervous Control --Sympathetic vasodilator nerves activated by"feed-forward" stimulation (in some animal species) --Sympathetic vasoconstrictor nerve activation - can attenuate vasodilation - "brake" preventing excess dilation (triggered by metabolic factors) -vasoconstriction of other beds and non-exercising muscle leads to redistribution of blood

Circulatory readjustments during exercise

1. Sympathetic discharge/parasympathetic withdrawal (increase AP) --Vasodilation - effected muscle --vasoconstriction - non-effected muscle 2. Increased arterial pressure (AP) ***small muscle exercise -- larger AP rise (sympathetic response occurs everywhere, but vasodilation occurs only in active muscles. E.g. weight lifting) ***large muscle or whole body exercise --smaller AP rise (extreme vasodilation in many muscles. E.g. swimming, running) 3. Increased cardiac output --Necessary to meet increased demand of oxygen and nutrients --As important as muscle strength in setting limits of the exercise

3. *****Formation of a clot: 3 steps

1. in response to rupture, complex cascade of chemical reaction is initiated ---> leads to production of PROTHROMBIN ACTIVATOR 2. prothrombin activator activates PROTHROMBIN to THROMBIN 3. THROMBIN converts fibrin into fibrin fibers that works with the platelets, blood cells, and plasma to form the clot. CASCADE 1. rupture 2. cascade reaction 3. prothrombin activator 4. prothrombin --> thrombin 5. thrombin converts fibrin --> fibrin fibers 6. clot

**Cardiac output response to increase VR

1. increase VR 2. Increase Right Atrial Pressure (increase filling) 3. increase atrial stretch --Stretching the sinus node --> increase heart rate --Bainbridge reflex --> sympathetic stimulus (increase BP) 4. increase contractile force 5. increase SV and CO ***Remember: Under most normal conditions, CO is mainly controlled by peripheral factors/venous return. The heart is not the primary controller of CO.

3. *****CLOT RETRACTION

1.Starts within a few minutes after clot is formed. 2.Clot begins to contract. 3.Expresses most of fluid from the clot within 20-60 min. Expressed fluid is called serum (no fibrinogen/clotting factors cannot clot) ****Platelets are required for clot retraction (Why? How?)

***KNOW: In a normal cardiac output curve, what is the maximum CO?

13L/min

**How fast does the formation of a clot occur?

15-20 seconds in SEVERE TRAUMA 1-2 minutes in MINOR CUTS

***KNOW: In a HYPEREFFECTIVE cardiac output curve, what is the maximum CO? Where does the curve shift to?

25L/min curve shift up 2.5x more than the normal 13L/min This is the point that the heart becomes the limiting factor

***KNOW: In a HYPOEFFECTIVE cardiac output curve, what is the maximum CO? Where does the curve shift to?

2L/min curve shift down

**What is the formation of the clot comprised of?

A mesh of fibrin fibers trapping blood cells, platelets, and plasma

****what is HEPARIN, and what does it do?

ANTICOAGULANT THAT PREVENTS BLOOD CLOTING ***conjugated polysaccharide, negative charge, little action unless combined with antithrombin III increases affinity of antithrombin III normally low concentration. In addition to thrombin removal, antithrombin III/heparin removes factors IX, X, XI, and XII.

***Frank - Starling Mechanism

Ability of heart to change its force of contraction and stroke volume in response to changes in venous return.

****KNOW: WHAT IS THE PROTHROMBIN ACTIVATOR COMPRISED OF?

Activated FACTOR X FACTOR 5 Ca++ PLATELET phospholipids

**Where will the heart be affected first when there is a decrease in blood flow to the heart?

Any decrease of blood flow to any area of the heart will first compromise sub endocardium and then spread towards epicardium.

V. Thrombocytopenia: low number of platelets

Bleeding from small capillaries and blood vessels, mucosal, skin Cause: Idiopathic Thrombocytopenic Purpura (ITP)- unknown cause, autoimmune (common)

*****KNOW: step 1 -- production of PROTHROMBIN ACTIVATOR

Both intrinsic and extrinsic pathways can activate Factor X. Both intrinsic and extrinsic pathways can act simultaneously.

During exercise, the SNS cause vasodilation in effected muscle and vasoconstriction to non-exercising muscle and system. What two part of the body that it will not be constricted during exercise?

CORONARIES AND BRAIN

**What is always required for the intrinsic and extrinsic pathway to occur?

Ca++

CHAPTER 20

Cardiac output, venous return and their regulation

****WHAT IS DINITROPHENOL?

DNP Metabolic stimulant---vasodilator

*****Mechanism of the Platelet Plug

Damage of vascular surface Sub-endothelial protein layer exposed Platelets come to contact collagen fibers via surface glycoproteins. 1. ADHESION Platelets swell, become sticky, contract and spread out. 2. ACTIVATION Release platelet agonists from granules Generate thrombin at site of vascular injury 3. AGGREGATION Promotes activation of new platelets and attract them 4. COAGULANT ACTIVITY Crosslinking of platelet aggregate by surface glycoprotein contractile elements, fibrin threads will provide stability

Cardiac function curve: ***heart is a limiting factor

Describes the ability of the heart to pump blood when AP is increasing The heart has limits to how much blood it can pump. The Cardiac Function Curve defines these limits.

Activation in response to blood damage or vessel rupture

EXTRINSIC INTRINSIC COMMON PATHWAY

**How is coronary blood flow into the heart muscle?

Epicardial arteries feed sub-endocardium. During systole, myocardial contraction compresses transverse arteries, so flow in subendocardial arteries is suppressed during systole. SLIDE 56

**ARE PLATELETS ACTIVE OR INACTIVE? Why?

Even though platelets do not have nucleus, it is an ACTIVE STRUCTURE SLIDE 6 Why? The platelet structure serves many functions. 1. ACTIVE CYTOPLASM -- it contains many important proteins and enzymes for cellular functions 2. CELL MEMBRANE FUNCTIONS -- CM contains receptors, coat of glycoproteins, phospholipids, and adenylate cyclase

***Effects of Nervous system in increase AP during exercise

Exercise --> + metabolism --> + vasodilatory products --> + vasodilation --> - resistance --> + flow What happens to BP? The BP at the effected tissues will decrease, HOWEVER, when you exercise, the SYMPATHETIC NERVOUS SYSTEM kicks in and causes vasoconstriction at other organs. There will be a simultaneous increase in HR, heart contractility, and pumping from venous constriction. THUS, AP WILL INCREASE TO ALLOW MORE MUSCLE BLOOD FLOWS Increase CO = Increase AP / decrease TPR

*What pathway is slower or faster?

Extrinsic is faster intrinsic is slower

****Extrinsic Pathway

FASTEST PATHWAY --- REQUIRES Ca++ 1. TISSUE TRAUMA 2. TISSUE FACTOR (activates Factor X using Ca++) 3. Activated Factor X -- (prothrombin activator) uses protease and splits pro-thrombin into thrombin (final clotting process) 4. FACTOR V -- promotes and accelerates thrombin formation (POSITIVE FEEDBACK)

*****KNOW: step 3 -- Conversion of fibrinogen into fibrin threads

Factor I -- fibrinogen formed in the liver a) fibrinogen (FI) is split into fibrinogen monomers b) automatic polymerization into long fibrin fiber threads (reticulum) c) fibrin stabilization (strong bonds requires circulating Factor XIII and fibrin stabilizing factor released from platelets and activated by thrombin ***KNOW PIC ON SLIDE 17

Anti-coagulant - Test tube

HEPARIN Clinical uses: hemodialysis heart-lung machine CALCIUM CHELATORS Bind calcium which is required for clotting Oxalate: toxic to the body-precipitates Ca+2 Citrate: can be used IV-rapidly removed by liver-usually used on transfused blood-deionizes Ca+2

**at rest, what does the heart metabolizes?

Heart metabolizes fatty acids at rest for own energy supply (about 70%).

***ischemic heart disease

Heart tissue not receiving adequate blood flow (low oxygen supply)

CHAPTER 36

Hemostasis and Blood Coagulation

**BE FAMILIAR -- Coagulation defects

I.Vitamin C deficiency Lack of stable collagen (elderly, alcoholics) II. Hepatic failure Almost all clotting factors are made in the liver III. Vitamin K deficiency Required for II (prothrombin), VII, IX, and X Fat malabsorption due to lack of bile secretion IV. Hemophilia Factor VIII (hemophilia A 1/10,000), Factor IX (hemophilia B 1/100,000) Linked to chromosome X V. Thrombocytopenia: low number of platelets VI. Disseminated Intravascular Clotting

1. Vascular Spasm (contraction)

IMMEDIATELY after a blood vessel has been cut/ruptured. Trauma to the vessel causes the vessel to contract. Vasoconstriction: local myogenic in response to damage to vascular wall local release of autacoid factors nervous reflexes (pain)

***What causes high CO / what are some examples?

INCREASED METABOLIC DEMAND IN TISSUES ****A. Beriberi: B1 deficiency, causes peripheral vasodilation due to insufficient nutrient usage B. Arteriovenous fistula (shunt): opening between major artery and vein, flow diverts C. Hyperthyroidism: basal metabolism increased, O2 consumption increases D. Anemia: reduced viscosity and reduced O2 delivery (vasodilation and metabolic need)

2. Platelet plug

If the cut is very small, the cut is sealed by platelet plug.

What is more important? Metabolic factors or neural influences to regulate blood flow?

Metabolic factors override neural influences in regards to coronary flow (just like skeletal muscle!).

CHAPTER 21

Muscle blood flow and cardiac output during exercise; the coronary circulation and ischemic heart disease

Hemostasis

PREVENTION OF BLOOD LOSS must be fluid must coagulate at the appropriate time -rapid -localized reversible

***Plasminogen inhibitors

Plasminogen activator inhibitor (PAI-1) -- inhibits TPA

****Platelets are required for clot retraction (Why? How?)

Platelets have factors that aids in both stabilizing the clot and also contracting the clot **contractile proteins in the cytoplasm of platelets are used for clot retraction contractile proteins: THROMBOSTENIN ACTIN MYOSIN ---compress the clot ---"squeezes" the clot ---retracts the edges of the blood vessel

**What is the final clotting process?

Production of thrombin

**What does Factor V do?

Promotes or accelerates thrombin formation

**What is prothrombin and where is is formed and found?

Prothrombin is Factor II Formed in the liver, and found in the plasma

****When does the COAGULATION CASCADE start? What are the effects?

Starts with trauma to the blood/tissue and contact of blood with damaged endothelial cells. 1. As clot forms, it extends into surrounding blood. 2. Clot will initiate positive feedback to promote more clotting.

***what is the tissue most susceptible to infarct and why?

Subendocardial tissue When there is damaged cardiac tissue, it no longer functions correctly. Fibrous scar tissue replaces dead myocardium. This is a hard tissue that will no longer contract and send blood down to the transverse artery.

****As AP increases, the CO increases, but there is a point that CO can no longer increase. Why?

THE HEART IS A LIMITING FACTOR As AP increases, the CO increases, but there is a point that CO can no longer increase. The reason is that the heart can only take so much before it can no longer increase CO. SLIDE 40

***what regulate the blood flow and CO?

TISSUE NEEDS

*****Cardiac function

The heart automatically pumps out what it receives from venous return (Frank Starling Mechanism) Additionally, stretching of the right atrium stretches the sinus node and triggers the Bainbridge reflex **raise heart rate.

**What is the relationship between CO and oxygen consumption during working out?

They both will increase in parallel the heart pumps to supply tissue needs

***Plasminogen activators

Tissue Plasminogen Activator (TPA) •slowly released after clot stops the bleeding, ***converts plasminogen into plasmin--will remove remaining unnecessary blood clot.

*****KNOW: step 2 -- conversion of prothrombin into thrombin

Using the prothrombin activator (FXa, V, Ca++, and phospholipids) prothrombin (FII) --> Thrombin (proteolytic enzyme)

**In equilibrium, what determines the amount of CO?

VENOUS RETURN you can only pump out the blood that is returned back to the heart

Explain how the ANS maintains AP?

When DNP is used, vasodilation occurs in the tissues. TPR decreases, this will lead to a decrease in AP and eventually decrease in CO. **in the absence of the sympathetic system: TO PREVENT CO DECREASE WHEN TPR DECREASES, the ANS is used to maintain the AP so the CO increases to be maintained.

VI. Disseminated Intravascular Clotting

Widespread abnormal bleeding and clot formation observed in patients with large amount of dying or damaged tissue (septicemia, septic shock). Uncontrolled coagulation and clot lysis leads to depletion of clotting factors. Thus, these patients have disseminated clots AND bleeding. Lethal in >85% of patients

****What is thrombomodulin? What does it do?

binds and removes thrombin it forms a thrombomodulin-thrombin complex the complex ACTIVATES PROTEIN C (INACTIVATES FACTOR V AND VIII)

***Acute coronary occlusion (clamped)

caused my myocardial ischemia and infarcted heart: thrombus (clot formation and coronary artery spasm)

Atherosclerotic plaques

cholesterol rich deposits beneath vascular endothelium. Unsmooth surface. May rupture through endothelium and lead to clot formation

***Plasminogen

circulating globulin in blood, gets trapped in clot PRECURSOR TO PLASMIN

coronary circulation

circulation of blood through the coronary blood vessels to deliver oxygen and nutrients to the heart muscle tissue two main feed arteries

*cardiac hypertrophy

enlargement of the heart by increases in muscle wall thickness or chamber size or both (long term increase in workload such as endurance exercise, increase in heart mass without damage)

**What does the ACTIVATED FACTOR X do?

it is a protease that splits prothrombin into thrombin

****What is thrombin? What does it do? (**slide 17)

it is a proteolytic enzyme function: acts on fibrinogen stimulates the release of fibrin stabilizing factor acts on prothrombin to INCREASE CLOTTING FACTORS **POSITIVE FEEDBACK

How is muscle blood flow to the skeletal muscle and heart achieved?

local control of vascular resistance in response to muscle tissue metabolic needs

fibrinolytic system

lysis of the clot

***Plasmin

proteolytic enzyme, similar to trypsin when activated it digest fibrin threads, fibrinogen, and other clotting factors SIGNIFICANCE: removal of tiny little clots

***What are collateral vessels and importance of it?

they are developed to improve ischemic tissues With a sudden occlusion, the anastomoses dilate within seconds to provide blood to distal regions, but this is usually less than 50% of the needed supply to keep cardiac muscle alive. Collateral vessels can further develop over time and after repeated episodes of ischemia (pre-conditioning). Collaterals do develop with time, and may avoid or diminished cardiac ischemia and consequences if the area affected is small. But..... *****They can develop atherosclerosis!!!

thromboembolic conditions

thrombus, embolus, embolism ***abnormal blood clot in blood vessel caused by: Rough endothelial cell surface Slow blood flow, or blocked blood flow Long-term bed immobilization, propping knee with pillow Pro-coagulant events (pregnancy, prolonged immobilization, trips) or diseases (sepsis) Examples: deep venous thrombosis (in legs), pulmonary embolism, artificial heart valves, disseminated intravascular coagulation in septic shock, atrial fibrillation.

Explain how CO is regulated in equilibrium

when the body is in equilibrium, CO regulation is the sum of blood flow regulation in all local tissues all local blood flow summates to form VR Heart pumps this returning blood back into the arteries

CHARACTERISTICS OF PLATELETS

· Formed in bone marrow, normal concentration = 150-350,000 /µl · Production regulated by thrombopoietin (liver and kidney) · Sequestered in spleen (over 50%, removed by macrophages) · Round or oval, 2-4 mm in diameter, ***life span 8-12 days · No nucleus, cannot reproduce, but has many functional characteristic of normal cells

endothelium

·protective barrier that separates blood cells from highly thrombogenic elements located deep within vascular wall. ·With a tear, blood comes in contact with exposed sub-endothelial matrix and collagen fibers which promotes formation of a hemostatic plug by vasoconstriction, activation of platelets and blood coagulation.

**Coagulation cascade characteristics (slide 10)

•Coagulation factors are circulating and in tissues •Several serine proteases: Most of them produced by liver, several require Vit K •3 protein cofactors (not enzymes) -Requires Ca 2+ -Localized to site of injury •Enzymatic cascade (amplification) •Reversible (via production of plasmin)