Pbl Exam 2 Case 3

Front 1

1. What does hemostasis mean?

Back 1

Prevention of blood loss

Front 2

2. When a vessel is severed or ruptured, what four mechanisms are needed to achieve hemostasis?

Back 2

1. Vascular constriction
2. Formation of a platelet plug
3. Formation of a blood clot as a result of blood coagulation
4. Eventual growth of fibrous tissue into the blood clot to close the hole in the vessel permanently

Front 3

3. What causes vascular contraction after rupture to a blood vessel?

Back 3

1. Local myogenic spasm
-initiated by direct damage to the vascular wall
-responsible for most of the vasoconstriction

2. Local autacoid factors from the traumatized tissues and blood platelets
-releases thromboxane A2

3. Nervous reflexes
-initiated by pain nerve impulses or other sensory impulses

In general, the more severely a vessel is traumatized, the greater the degree of vascular spasm

Front 4

4. Platelets

How are they formed?

What is their concentration in the blood?

Back 4

Minute discs 1-4 um in diameter

Formed in the bone marrow from megakaryocytes, which are extremely large cells of the hematopoietic series in the marrow; the megakaryocytes fragment into the minute platelets either in the bone marrow or soon after entering the blood

The normal concentration in the blood is between 150,000 and 300,000 per uL

Front 5

5. What are the characteristics of platelets?

How are they related to whole cells?

Back 5

1. Do not have nuclei and cannot reproduce
2. Actin and myosin molecules similar to those found in muscle cells, and thrombosthenin which causes the platelets to contract
3. Residuals of both the ER and golgi apparatus that synthesize enzymes and store large quantities of Ca
4. Mitochondria and enzymes that form ATP and ADP
5. Enzymes that synthesize prostaglandins, which causes vascular and local tissue reactions
6. Fibrin-stabilizing factor
7. Growth factor that causes vascular endothelial cells, vascular smooth muscle cells and fibroblasts to multiply and grow

Front 6

6. Cell membrane of platelets

Back 6

On its surface is a coat of glycoproteins that repulses adherence to normal endothelium and yet causes adherence to injured areas of the vessel wall

Also contains large amounts of phospholipids that activate multiple stages in the blood clotting process

Front 7

7. What happens when platelets come in contact with a damaged vascular surface?

Back 7

When platelets come in contact with a damaged vascular surface, especially with collagen fibers, the platelets immediately change.

1. They begin to swell
2. They assume irregular forms with numerous irradiating pseudopods protruding form their surfaces
3. Their contractile proteins contract forcefully and cause the release of granules that contain multiple active factors
4. They become sticky so that they adhere to collagen in the tissues and to vWF that leaks into the traumatized tissue from the plasma
5. They secrete large quantities of ADP
6. Their enzymes form thromboxane A2
7. The ADP and thromboxane in turn act on nearby platelets to activate them as well and recruits them to the injured site

Front 8

8. How are trauma and clotting time related?

Back 8

The clot begins to develop in 15-20 secs if the trauma to the vascular wall has been severe

If the trauma is minor, the clot forms in 1 to 2 minutes

Front 9

9. When a blot clot has formed, what two options does it have?

Back 9

1. It can become invaded by fibroblasts which subsequently form connective tissue all thru the clot

2. It can dissolve

Front 10

10. Basic theory of blood coagulation

Back 10

You've got procoagulants and anticoagulants

Whether blood will coagulate depends on the balance between these two groups of substances

In the blood stream, the anticoagulants normally predominate so that blood does not coagulate while it is circulating in the blood vessels. But when a vessel is ruptured, procoagulants from the area of tissue damage become "activated" and override the anticoagulants, and then a clot does develop.

Front 11

11. General mechanism of blood coagulation - three steps

Back 11

Clotting takes place in three essential steps:
1. In response to rupture of the vessel or damage to the blood itself, a complex cascade of chemical reactions occurs in blood. The net result is formation of a complex of activated substances called prothrombin activator

2. The prothrombin activator catalyzes conversion of prothrombin into thrombin

3. The thrombin acts as an enzyme to convert fibrinogen into fibrin fibers that enmesh platelets, blood cells, and plasma to form the clot.

Front 12

12. Prothrombin

Back 12

Plasma protein, an alpha2-globulin, having a molecular weight of 68,700.

Present in the normal plasma in a concentration of about 15 mg/dl.

Can split into smaller compounds, i.e. thrombin

Formed continuously in the liver, and is continually being used throughout the body for blood clotting; if the liver fails to produce it then normal blood coagulation is halted

Vitamin K is required by the liver for normal formation of prothrombin as well as for formation of other factors.

Front 13

13. Conversion of prothrombin to thrombin

Back 13

1. Prothrombin activator is formed as a result of rupture of blood vessel or as a result of damage to special substances in the blood.
2. Prothrombin activator, in the presence of sufficient amounts of ionic calcium, causes conversion of prothrombin to thrombin
3. The thrombin causes polymerization of fibrinogen molecules into fibrin fibers within another 10-15 s.

Thus, the rate limiting factor in causing blood coagulation is usually the formation of prothrombin activator and not the subsequent reactions beyond that point, because these terminal steps normally occur rapidly to form the clot itself.

Side note: platelets also play important roles in this conversion b/c much of the prothrombin first attaches to prothrombin receptors on the platelets already bound to the damaged tissue.

Front 14

14. Fibrinogen

Back 14

A high molecular weight protein that occurs in the plasma in quantities of 100 to 700 mg/dl.

Formed in the liver, and liver disease can decrease the concentration in the blood.

B/c of its large molecular size, little fibrinogen normally leaks from the blood vessels into the interstitial fluids, and because fibrinogen is one of the essential clotting factors, interstitial fluids ordinarily do not coagulate.

When the permeability of the capillaries becomes pathologically increased, it does leak into the tissue fluids to allow clotting of these fluids in much the same way that plasma and whole blood can clot.

Front 15

15. Action of thrombin on fibrinogen

Back 15

Forms fibrin.

Thrombin is an enzyme w/weak proteolytic capabilities; it acts on fibrinogen to remove four low molecular weight peptide from each molecule of fibrinogen, forming one molecule of fibrin monomer that has the automatic capability to polymerize to form fibrin fibers.

Therefore, many fibrin monomer molecules polymerize within seconds into long fibrin fibers that constitute the reticulum of the blood clot.

Front 16

16. Fibrin monomer bonding

Back 16

In the early stages of polymerization, the fibrin monomers are held together by weak non covalent hydrogen bonding, and the newly forming fibers are not cross-linked w/one another - the clot is weak and can be broken apart easily.

Later, a substance called fibrin-stabilizing factor is released from platelets entrapped in the clot. This stabilizing factor must be activated by thrombin.

Once activated, it operates as an enzyme to cause covalent bonds between more and more of the fibrin monomers and adds cross linkage, thus adding to the strength of the fibrin meshwork.

Front 17

17. Clot retraction

Back 17

Within a few minutes after a clot is formed, it beings to contract and usually expresses most of the fluid from the clot within 20-60 min.

The fluid expressed is called serum because all its fibrinogen and most of the other clotting factors have been removed.

Platelets are necessary for clot retraction to occur as they activate platelet thrombosthenin, actin, and myosin molecules, which are all contractile proteins in the platelets and causes strong contraction of the platelet spicules attaches to the fibrin.

This helps compress the fibrin meshwork into a smaller mass

The contraction is activated and accelerated by thrombin as well as by calcium ions released from the organelles of platelets.

Front 18

18. Vicious circle of clot formation

Back 18

Once a blood clot has started to develop, it normally extends within minutes into the surrounding blood.

The clot itself initiates a vicious circle to promote more clotting.

One of the most important causes of this is the fact that the proteolytic action of thrombin allows it to act on many of the other blood-clotting factors in addition to fibrinogen.

For instance, thrombin has a direct proteolytic effect on prothrombin itself, tending to convert this into still more thrombin, and it acts on some of the blood-clotting factors responsible for formation of prothrombin activator.

Once a critical amount of thrombin is formed, a vicious circle develops that causes still more blood clotting and more and more thrombin to be formed; thus the blood clot continues to grow until blood leakage ceases.

Front 19

19. How is prothrombin activator formed?

Back 19

By two ways that interact constantly with one another:

1. Extrinsic pathway that begins with trauma to the vascular wall and surrounding tissues

2. Intrinsic pathway that begins in the blood itself

Blood clotting factors play major roles and most are inactive forms of proteolytic enzymes; when converted to the active forms, their enzymatic actions cause the successive, cascading reactions of the clotting process.

Front 20

20. Extrinsic pathway

Back 20

1. Release of tissue factor; this factor is composed especially of phospholipids from the membranes of the tissue plus a lipoprotein complex that functions mainly as a proteolytic enzyme.

2. Activation of Factor 10 via Factor 7 and tissue factor
-The lipoprotein complex of tissue factor further compelxes with blodo coagulation Factor 7 and, in the presence of calcium ions, acts enzymatically on Factor 10 to form activated Factor 10a

3. Effect of activated Factor 10a to form prothrombin activator via Factor 5
-Factor 10a combines w/tissue phospholipids as well as with additional phospholipids released from platelets as well as with Factor 5 to form the complex called prothrombin activator.
-Within a few seconds, in the presence of calcium ions, this splits prothrombin into thrombin and the clotting process proceeds.

Front 21

21. Extrinsic pathway in a nutshell

Back 21

Tissue trauma
↓
Tissue factor
↓
7 → 7a; via tissue factor
↓
10 → 10a; via 7a and calcium ions
↓
Common pathway

Front 22

22. Intrinsic pathway

Back 22

1. Blood trauma causes: activation of Factor 12 and release of platelet phospholipids
2. Activation of Factor 11 which requires HMW kininogen and is accelerated by prekallikrein
3. Activation of Factor 9 via Factor 11a, acting in concert with activated Factor 8a and with the platelet phospholipids and Factor 3 from the traumatized platelets activated Factor 10.
5. Action of activated Factor 10a to form prothrombin activator via common pathways

Front 23

23. Intrinsic pathway in a nutshell

Back 23

Blood trauma
↓
12 → 12a; via blood trauma
↓
11 → 11a; via 12a and HMW kininogen and prekallikrein
↓
9 → 9a; via 11a
↓
10 → 10a; via 8a which provides surface area for 9a to activate 10a with Ca+ ions and phospholipids

Front 24

24. Common cascade

Back 24

Activated Factor 10a combines with Factor 5 and platelet or tissue phospholipids to form the complex called prothrombin activator

The prothrombin activator in turn initiates within seconds the cleavage of prothrombin to form thrombin, thereby setting into motion the final clotting process.

Front 25

25. Role of calcium ions in the intrinsic and extrinsic pathways

Back 25

Except for the first two steps in the intrinsic pathway, calcium ions are required for promotion or acceleration of all the blood-clotting reactions.

Without these ions, blood clotting by either pathway does not occur. This is why deionizing the calcium by causing it to react with substances such as citrate ion or oxalate ions prevents blood from clotting outside the body.

Front 26

26. Important difference between the extrinsic and intrinsic pathways

Back 26

The extrinsic pathway can be explosive; once initiated, its speed of completion to the final clot is limited only by the amount of tissue factor released from the traumatized tissues and by the quantities of Factors 10, 7, and 5 in the blood.
With severe tissue trauma, clotting can occur in as little as 15 seconds.

The intrinsic pathway is much slower to proceed, usually requiring 1 - 6 minutes to cause clotting.

Front 27

27. What are the most important factors for preventing clotting in the normal vascular system?

Back 27

1. The smoothness of the endothelial cell surface, which prevents contact activation of the intrinsic clotting system

2. A layer of glycocalyx on the endothelium which repels clotting factors and platelets, thereby preventing activation of clotting

3. A protein bound with the endothelial membrane, thrombomodulin, which binds thrombin. When bound to thrombin, this slows the clotting process and activates protein C, which acts as an anticoagulant by inactivated activated Factors 5 and 8.

Front 28

28. Endothelial wall damage

Back 28

When the endothelial wall is damaged, its smoothness and its glycocalyx-thrombomodulin layer are lost, which activates both Factor 12 and the platelets, thus settingoff the intrinsic pathway of clotting.

If Factor 12 and platelets come in contact w/the subendothelial collagen, the activation is even more powerful.

Front 29

29. Antithrombin II

Back 29

Among the most important anticoagulants in the blood itself are those that remove thrombin from the blood.

The most powerful of these are:
1. The fibrin fibers that themselves are formed during the process of clotting
2. An alpha-globulin called antithrombin III or antithrombin-heparin cofactor

The thrombin that does not absorb to the fibrin fibers soon combines w/antithrombin III, which further blocks the effect of thrombin on the fibrinogen and then also inactivates the thrombin itself.

Front 30

30. Heparin

Back 30

A powerful anticoagulant that occurs naturally in the blood and is used widely as a pharmacological agent to prevent intravascular clotting.

The heparin molecule is a highly negatively charged polysaccharide. When it combines with antithrombin III, the effectiveness of antithrombin III for removing thrombin is increased by 100x - 1,000x and thus it acts as an anticoagulant.

The complex of heparin and antithrombin III removes several other activated factors; Factors 12, 11, 10, and 9.

Front 31

31. Mast cells and basophils

Back 31

Heparin is produced in large quantities by mast cells located in tissue surrounding the capillaries in the lungs and liver; this is a good location b/c these areas receive many embolic clots formed in slowly flowing venous blood - mast cell release of heparin prevents further growth of clots.

Basophils also release smaller quantities of heparin into the plasma.

Front 32

32. Plasminogen

Back 32

AKA profibrinolysin

When activated, becomes a substance called plasmin.

Front 33

33. Plasmin

Back 33

AKA fibrinolysin

Plasmin is a proteolytic enzyme that resembles trypsin, the most important proteolytic digestive enzyme of pancreatic secretion

Digests fibrin fibers and some other protein coagulants such as fibrinogen, Factor 5, Factor 8, prothrombin, and Factor 12.

Therefore, whenever plasmin is formed, ti can cause lysis of a clot by destroying many of the clotting factors.

Front 34

34. Lysis of clots

Back 34

The injured tissues and vascular endothelium very slowly release a powerful activator called tissue plasminogen activator (t-PA) that a few days later, after the clot has stopped the bleeding, eventually converts plasminogen to plasmin, which in turn removes the remaining unnecessary blood clot.

Thus, an important function of the plasmin system is to remove minute clots from millions of tiny peripheral vessels that eventually would become occluded were there no way to clear them.

Front 35

35. Three important types of bleeding tendencies

Back 35

1. Vitamin K deficiency

2. Hemophilia

3. Thrombocytopenia

Front 36

36. What does vitamin K deficiency lead to?

Back 36

Decreased levels of:
1. Prothrombin
2. Factor 7
3. Factor 9
4. Factor 10

Front 37

37. Synthesis of vitamin K

Back 37

Continually synthesized in the intestinal tract by bacteria.

However, in GI disease, vitamin K deficiency often occurs as a result of poor absorption of fats from the GI tract since vitamin K is fat-soluble.

Front 38

38. What is the most prevalent cause of vitamin K deficiency?

Back 38

Failure of the liver to secrete bile into the GI tract due to bile duct obstruction or liver disease.

Lack of bile prevents adequate fat digestion and absorption.

Liver disease often causes decreased production of prothrombin and some other clotting factors both because of poor vitamin K absorption and b/c of diseased liver cells.

Side note: this is the reason vitamin K is injected into all surgical patients w/liver disease 4-8 hours before operation in order to prevent excessive bleeding.

Front 39

39. Hemophilia

Back 39

A bleeding disease that occurs almost exclusively in males.

In 85% of cases, it is caused by an abnormality or deficiency of Factor 8; this type of hemophilia is called "Hemophilia A" or "classic hemophilia"

In the other 15% of cases, it is caused by a defiency of Factor 9.

Both of these factors are transmitted genetically by way of the female chromosome, i.e. X linked.

Front 40

40. Factor 8

Back 40

Has two active components, a large component w/a molecular weiht in the millions and a smaller component w/a molecular weight of 230,000.

This smaller component is most important in the intrinsic pathway for clotting, and it is deficiency of this factor that causes classic hemophilia.

Front 41

41. Therapy for prolonged bleeding in patients with classic hemophilia

Back 41

The only therapy that is truly effective is injection of purified Factor 8.

The cost of Factor 8 is high, and its availability is limited b/c it can be gathered only from human blood in very small quantities.

Front 42

42. Thrombocytopenia

Back 42

Means the presence of very low numbers of platelets in the circulating blood.

People w/this disease have a tendency to bleed, as do hemophiliacs, except that the bleeding is usually from many small venules or capillaries, rather than from larger vessels as in hemophilia.

As a result, small punctate hemorrhages occur throughout all the body tissues, esp in the skin which displays purplish blotches, giving the disease the name "thrombocytopenic purpura"

Front 43

43. Suspicion of thrombocytopenia without making specific platelet counts

Back 43

If the person's blood fails to retract, because clot retraction is normally dependent on release of multiple coagulation factors from the large numbers of platelets entrapped in the fibrin mesh of the clot.

Front 44

44. Most common form of thrombocytopenia

Back 44

Idiopathic thrombocytopenia

In most of these people, specific antibodies have formed and react against the platelets themselves to destroy them.

Front 45

45. Therapy for bleeding in patients with thrombocytopenia

Back 45

Transfusions of fresh whole blood which contain large numbers of platelets.

Also, splenectomy is often helpful, sometimes effecting almost complete cure b/c the spleen normally removes large numbers of platelets from the blood.

Front 46

46. Difference between thrombi and emboli

Back 46

An abnormal clot that develops in a blood vessel is called a thrombus.

Once a clot has developed, continued flow of blood past the clot cause the clot to break away and flow w/the blood. These freely flowing clots are known as emboli.

Also, emboli that originate in large arteries or in the left side of the heart can flow peripherally and plug arteries or arterioles in the brain, kidneys, or elsewhere.

Emboli that originate in the venous system or in the right side of the heart generally flow into the lungs and cause pulmonary arterial embolism.

Front 47

47. Cause of thromboembolic conditions

Back 47

1. Any roughened endothelial surface of a vessel - as caused by arteriosclerosis, infection or trauma - is likely to initiate clotting
2. Slow flow of blood predisposes blood to clot

Front 48

48. Use of t-PA in treating intravascular clots

Back 48

t-PA (Tissue plasminogen activator) is delivered directly to a thrombosed area thru a catheter. There, ti is effective in activating plasminogen into plasmin, which in turn can dissolve some intravascular clots.

Must be used promptly (i.e. within first hour of clot)

Front 49

49. Disseminated intravascular coagulation (DIC)

Back 49

Occasionally, the clotting mechanism becomes activated in widespread areas of circulation, giving rise to DIC.

This often results from the presence of large amounts of traumatized or dying tissue in the body that releases great quantities of tissue factor into the blood.

Occurs especially in patients with widespread septicemia, in which either circulating bacteria or bacterial toxins - esp endotoxins - activate the clotting mechanism.

Paroxysmal effect of DIC is that excessive bleeding can occur; since the clotting factors are removed by the widespread clotting, too few procoagulants remain to allow normal hemostasis of the remaining blood

Front 50

50. Heparin as an IV anticoagulant

Back 50

Extracted from several different animal tissues and prepared in almost pure form.

Injection of relatively small quantities causes the blood-clotting time to increase from a normal of about 6 minutes to 30 or more minutes.

This change in clotting time occurs instantaneously, thereby preventing or slowing further development of a thromboembolic condition

Action of heparin lasts about 1.5 to 4 hours. The injected heparin is destroyed by heparinase.

Front 51

51. Coumarins as anticoagulants

Back 51

When a coumarin, such as warfarin, is given to a patient, the plasma levels of prothrombin and Factors 7, 9, and 10, all formed by the liver, begin to fall.

Warfarin causes this effect by competing with vitamin K for reactive sites in the enzymatic processes for formation of prothrombin and the other three clotting factors, thereby blocking the action of vitamin K.

After admin of effective dose of warfarin, the coagulant activity of the blood decrease to about 20-50% normal.

However, the coagulation process is not blocked immediately but must await the natural consumption of the prothrombin and the other affected coagulation factors already present in the plasma.

Normal coagulation usually returns 1-3 days after discontinuing coumarin therapy.

Front 52

52. How can we prevent blood from clotting in test tubes?

Back 52

In glass test tubes, the blood normally clots in about 6 minutes as the glass surface allows contact activation of the platelets and Factor 12, with rapid development of clots.

However, blood collected in siliconized containers often does not clot for 1 hour or more.

Front 53

53. How else can we prevent blood clotting outside of the body?

Back 53

1. Heparin (dialysis, heart-lung machines)
2. Oxalate compounds cause precipitation of calcium oxalate from the plasma and thereby decreases the ionic calcium level so much that blood coagulation is blocked.
3. Citrate ions mixed w/blood in the form of sodium, ammonium, or potassium citrate which combines with calcium in the blood to caused an un-ionized calcium compound. The lack of ionic calcium prevents coagulation.

Citrate anticoagulants are better than oxalates b/c oxalates are more toxic to the body; however, liver damage can result in too much citrates in the blood which lead to tetany and convulsive death.

Front 54

54. Methods used to determine blood clotting times

Back 54

Collect blood in a chemically clean glass test tube and then tip the tube back and forth about every 30 s until the blood has clotted. By this method, the normal clotting time is 6-10 min.

Unfortunately, the clotting time varies widely depending on the method used for measuring it, so it is no longer used in many clinic.

Instead, measurements of the clotting factors themselves are made, using sophisticated chemical procedures.

Front 55

55. Prothrombin time

Back 55

This gives an indication of the concentration of prothrombin in the blood.

Blood removed from the patient is immediately oxalated so none of the prothrombin can change into thrombin.

Then, a large excess of calcium ion and tissue factor is mixed with the oxalated blood. The excess calcium nullifies the effect of the oxalate, and the tissue factor activates the prothrombin-to-thrombin reaction by means of the extrinsic clotting pathway.

The time required for coagulation to take place is known as the prothrombin time. The shortness of the time is determined mainly by prothrombin concentration.

Normal prothrombin time is 12 s

In each lab, a curve relating prothrombin concentration to prothrombin time is used in order to determine the prothrombin quantity in blood.

Front 56

56. Other methods used to determine blood clotting times via clotting factors

Back 56

In each of these tests, excesses of calcium ions and all the other factors BESIDES THE ONE BEING TESTED are added to oxalated blood all at once.

Then the time required for coagulation is determined in the same manner as for prothrombin time.

If the factor being tested is deficient, the coagulation time is prolonged. The time itself can then be used to quantitate the concentration of the factor.

Front 57

57. Pulmonary vessels

Back 57

The PA extends only 5 cm beyond the apex of the right ventricle and then divides into right and left main branches that supply blood to the respective lungs.

The PA is thin, w/a wall thickness 1/3 that of the aorta. The PA branches are very short, and all PA's have larger diameters than their counterpart systemic arteries.

The pulmonary veins are also short; they immediately empty their effluent blood into the left atrium, to be pumped by the left heart thru the systemic circulation

Front 58

58. Significant feature of the pulmonary arterial tree

Back 58

Has a large compliance due to the vessels being thin and distensible

Avgs almost 7 ml/mm Hg, which is similar to that of the entire systemic arterial tree.

This large compliance allows the pulmonary arteries to accommodate the stroke volume output of the right ventricle.

Front 59

59. Bronchial vessels

How about left ventricular output vs. right ventricular output?

Back 59

Blood flows to lungs thru small bronchial arteries amounting to about 1-2% of total CO.

This blood is oxygenated blood, in contrast to the partially deoxygenated blood in the PA's.

After this bronchial and arterial blood has passed thru the supporting tissues, it empties into the pulmonary veins, and enters the left atrium, rather than passing back to the right atrium.

Therefore, the flow into the left atrium and the left ventricular output are about 1-2% greater than the right ventricular output.

Front 60

60. Lymphatics in the lung

Back 60

Present in all the supporting tissues of the lung, beginning in the connective tissue spaces that surround the terminal bronchioles, coursing to the hilum of the lung, and emptying mainly into the right thoracic lymphatic duct.

Helps remove particulate matter and prevents pulmonary edema by removing plasma proteins leaking into the lung capillaries.

Front 61

61. Normal systolic pressure in the right ventricle

Back 61

Averages about 25 mm Hg

Front 62

62. Normal diastolic pressure in the right ventricle

Back 62

Averages about 0 - 1 mm Hg

Front 63

63. Pressure changes in the pulmonary arteries during systole and diastole

Back 63

During systole, the pressure in the PA is essentially equal to the pressure in the right ventricle.

However, after the pulmonary valve closes at the end of systole, the ventricular pressure falls rapidly, whereas the pulmonary arterial pressure falls more slowly as blood flows thru the capillaries of the lungs.

Systolic PA pressure = 25 mm Hg
Diastolic PA pressure = 8 mm Hg

Mean PA pressure = 15 mm Hg

Front 64

64. Mean pressure in the left atrium and major pulmonary veins

How is this measured?

Back 64

2 mm Hg

Difficult to measure using direct measuring device b/c it is difficult to pass catheter thru the heart chambers into the left atrium.

However, the left atrial pressure can often be estimated by measuring the pulmonary wedge pressure.

Front 65

65. Pulmonary wedge pressure

Back 65

A catheter is inserted first thru a peripheral vein to the right atrium, then thru the right side of the heart and thru the pulmonary artery into one of its small branches, finally pushing the catheter until it wedges tightly in the small branch.

The pressure measured is called the wedge pressure, and is normally about 5 mm Hg.

This makes a direct connection w/the pulmonary capillaries, and is usually only 2 - 3 mm Hg greater than the left atrial pressure.

Often used to study changes in pulmonary capillary pressure and left atrial pressure in patients w/congestive heart failure.

Front 66

66. Blood volume of the lungs

Back 66

About 450 mL, which is about 9% of the total blood volume of entire circulatory system.

Approx 70 mL of this blood volume is in the pulmonary capillaries, and the remainder is divided about equally between the pulmonary arteries and veins.

Front 67

67. How are the lungs a type of "blood reservoir"?

Back 67

Under various physiological and pathological conditions, the quantity of blood in the lungs can vary from a little as 1/2 normal up to 2x normal.

When a person exhales forcefully, as much as 250 mL of blood can be expelled from the pulmonary circulation

Also, loss of blood from the systemic circulation can be partly compensated for by the automatic shift of blood form the lungs into the systemic vessels.

Front 68

68. What happens to the shift of blood when the left side of the heart fails or increased resistance to blood flow thru the mitral valve occurs?

Back 68

Causes blood to dam up in the pulmonary circulation, sometimes increases the blood volume as much as 100% and causing large increases in the pulmonary vascular pressures.

B/c the volume of the systemic circulation is about 9x that of the pulmonary system, the shift of blood from one system to the other affects the pulmonary system greatly but usually has only mild systemic circulatory effects.

Front 69

69. What is essentially equal to the blood flow thru the lungs?

Back 69

The cardiac output.

Therefore, factors that control CO, mainly peripheral factors, also control pulmonary blood flow.

Front 70

70. What happens when the concentration of O2 in the air of the alveoli decreases below normal (i.e. below 73 mm Hg PO2)?

Back 70

The adjacent blood vessels constrict, with the vascular resistance increasing more than 5x at extremely low O2 levels.

This is opposite to the effect observed in systemic vessels, which dilate rather than constrict.

It is believed that low O2 causes some vasoconstrictor substance to be released possibly by the alveolar epithelial cells when they become hypoxic.

Front 71

71. Why is vasoconstriction in the lungs due to low O2 important?

Back 71

It distributes blood flow to where it is most effective.

That is, if some alveoli are poorly ventilated so that their O2 concentration becomes low, the local vessels constrict. This causes the blood to flow thru other areas of the lungs that are better aerated.

Front 72

72. Differences in pulmonary blood pressures are due to what?

Back 72

Caused by differences in hydrostatic pressure - that is, the weight of the blood itself in the blood vessels.

At the apex of the lungs, the pressure is much less than at the bottom of the lungs.

Front 73

73. Blood flow at different levels in the lungs of an upright person at rest and during exercise.

Back 73

When a person is at rest, the blood flow is very low at the top of the lungs; most of the flow is thru the bottom of the lung.

During exercise, blood flow to all levels increases.

Front 74

74. Zone 1 blood flow

Back 74

No blood flow during all portions of the cardiac cycle b/c the local alveolar capillary pressure in that area of the lung never rises higher than the alveolar pressure during any part of the cardiac cycle.

Front 75

75. Zone 2 blood flow

Back 75

Intermittent blood flow only during the pulmonary arterial pressure peaks b/c the systolic pressure is then greater than the alveolar air pressure, but the diastolic pressure is less than the alveolar air pressure.

Front 76

76. Zone 3 blood flow

Back 76

Continuous blood flow because the alveolar capillary pressure remains greater than alveolar air pressure during the entire cardiac cycle.

Front 77

77. Normal distribution of blood flow zones in the lungs

Back 77

Normally, the lungs have only zones 2 and 3 blood flow

Zone 2 in the apices

Zone 3 in all the lower areas.

Front 78

78. Why is zone 2 at the lung apices?

Back 78

Blood flows through the apical part of the lung is intermittent, with flow during systole but cessation of flow during diastole; this is called zone 2 blood flow.

Zone 2 blood flow begins in the normal lungs about 10 centimeters above the midlevel of the heart and extends from there to the top of the lungs.

Front 79

79. When, then, does zone 1 blood flow occur?

Back 79

Only under abnormal conditions.

Occurs when either the pulmonary systolic arterial pressure is too low or the alveolar pressure is too high to allow flow.

Front 80

80. During exercise, what happens to the blood flow zone at the lung apices?

Back 80

There is an increase in blood flow to the top of the lungs and this increase is much greater than the increases in blood flow to the lower part of the lungs.

Thus, the pressure differences allow the pulmonary vascular pressures to rise enough during exercise to convert the lung apices from zone 2 pattern into a zone 3 pattern of flow.

Front 81

81. During heavy exercise, how is the increased blood flow accommodated in the lungs?

Back 81

Three ways:

1. Increasing the number of open capillaries, sometimes as much as 3x

2. Distending all the capillaries and increasing the rate of flow through each capillary more than twofold

3. Increasing the pulmonary arterial pressure.

In the normal person, the first two changes decrease pulmonary vascular resistance so much that the pulmonary arterial pressure rises very little, even during maximum exercise.

This conserves the energy of the right side of the heart and also prevents development of pulmonary edema.

Front 82

82. What happens to the pulmonary circulation when the left atrial pressure rises?

What causes the left atrial pressure to rise?

Back 82

Left sided heart failure causes this.

Normal left atrial pressure almost never rises above +6 mm Hg.

However, when the left side of heart fails, blood begins to dam up in the left atrium, and this causes the left atrial pressure to rise to 40 - 50 mm Hg.

Any left atrial pressure above 7 or 8 mm Hg causes an equal increase in pulmonary arterial pressure, thus causing an increased load on the right heart.

Most left atrial pressures above 30 mm Hg are likely to develop pulmonary edema.

Front 83

83. What is the mean pulmonary capillary pressure?

Back 83

7 mm Hg

Front 84

84. What are the quantitative differences between fluid exchange in lung capillary membranes and peripheral tissues?

Back 84

1. The pulmonary capillary pressure is low, about 7 mm Hg, in comparison w/a higher functional capillary pressure in the peripheral tissues of about 17 mm Hg.

2. The interstitial fluid pressure in the lung is slightly more negative than that in the peripheral subcutaneous tissue

3. The pulmonary capillaries are relatively leaky to protein molecules, so that the colloid osmotic pressure of the pulmonary interstitial fluid is about 14 mm Hg, in comparison w/less than half this value in the peripheral tissues.

4. The alveolar walls are extremely thin, and the alveolar epithelium covering the alveolar surfaces is so weak that is can be ruptured by any positive pressure in the interstitial spaces greater than alveolar air pressure

Front 85

85. What is the mean filtration pressure at the pulmonary capillary membrane?

Back 85

+1 mm Hg

This causes a slight continual flow of fluid from the pulmonary capillaries into the interstitial spaces, and except for a small amount that evaporates in the alveoli, this fluid is pumped back to the circulation thru the pulmonary lymphatic system.

Front 86

86. How are the alveoli kept "dry"?

Back 86

Experiments have shown that there are always openings between the alveolar epithelial cells thru which even large protein molecules, as well as water and electrolytes can pass.

However, the pulmonary capillaries and the pulmonary lymphatic system normally maintain a slight negative pressure in the interstitial spaces, and thus whenever extra fluid appears in the alveoli, it is sucked mechanically into the lung interstitium.

Thus, under normal conditions, the alveoli are kept dry, except for a small amount of surfactant that seeps from the epithelium onto the lining surfaces of the alveoli to keep them moist.

Front 87

87. Physiologically, what causes pulmonary edema?

Back 87

Any factor that causes the pulmonary interstitial fluid pressure to rise from the negative range into the positive range will cause rapid filling of the pulmonary interstitial spaces and alveoli with large amounts of free fluid.

Front 88

88. Most common causes of pulmonary edema

Back 88

1. Left sided heart failure or mitral valve disease, with consquent great increases in pulmonary venous pressure and pulmonary capillary pressure and flooding of the interstitial spaces and alveoli.

2. Damage to the pulmonary blood capillary membranes caused by infections such as pneumonia or by breathing noxious substances such as chlorine gas or sulfur dioxide gas. Each of these causes rapid leakage of both plasma proteins and fluid out of the capillaries and into both the lung interstitial spaces and the alveoli.

Front 89

89. Pulmonary edema safety factor

What is the normal colloid osmotic pressure?

Back 89

The pulmonary capillary pressure normally must rise to a value at least equal to the colloid osmotic pressure of the plasma inside the capillaries before significant pulmonary edema will occur.

Normal colloid osmotic pressure is 28 mm Hg.

One can predict that the pulmonary capillary pressure must rise from the normal level of 7 mm Hg to more than 28 mm Hg to cause pulmonary edema, giving an ACUTE SAFETY FACTOR AGAINST PULMONARY EDEMA at 21 mm HG

Front 90

90. Safety factor against pulmonary edema in chronic conditions

Back 90

When the pulmonary capillary pressure remains elevated chronically, the lungs become even more resistant to pulmonary edema b/c the lymph vessels expand greatly, increasing their capability of carrying fluid away from the interstitial spaces.

Thus, in patients w/chronic mitral stenosis, pulmonary capillary pressures of 40 to 45 mm Hg have been measured w/o the development of lethal pulmonary edema

Front 91

91. Dynamics of fluid exchange in the pleural space

Back 91

The pleural membrane is a porous, mesenchymal, serous membrane thru which small amts of interstitial fluid transude continually into the pleural space.

These fluids carry w/them tissue proteins, giving the pleural fluid a mucoid characteristic, which is what allows extremely easy slippage of the moving lungs.

Front 92

92. Excess fluid pumped away from the pleural space goes to where?

Back 92

1. The mediastinum

2. The lateral surfaces of the parietal pleura

3. The superior surface of the diaphragm.

Thus, the pleural space is called a "potential" space because it normally is so narrow that it is not obviously a physical space.

Front 93

93. What must the pleural space maintain in order to keep the lungs expanded?

Back 93

A pressure at least as negative as -4 mm Hg

Front 94

94. Pleural effusion

What causes pleural effusion?

Back 94

Means the collection of large amounts of free fluid in the pleural space.

Causes include:
1. Blockage of lymphatic drainage from the pleural cavity
2. Cardiac failure
3. Greatly reduced plasma colloid osmotic pressure
4. Infection or any other cause of inflammation of the surfaces of the pleural cavity

Front 95

95. In order for diffusion to occur, what must be present?

Back 95

A source of energy

This is provided by the kinetic motion of the molecules themselves.

Front 96

96. Net diffusion of a gas occurs in which direction?

Back 96

If a gas chamber or a solution has a high concentration of a particular gas at one end of the chamber and a low concentration at the other end, net diffusion of the gas will occur from the high-concentration area toward the low-concentration area.

Reason: far more molecules at high-concentration end of the chamber to diffuse toward the low-concentration end than there are molecules to diffuse in the opposite direction.

Front 97

97. Partial pressures of individual gases

Back 97

The pressure is directly proportional to the concentration of the gas molecules.

Thus, the pressure of a gas acting on the surfaces of the respiratory passages and alveoli is proportional to the summated force of impact of all the molecules of that gas striking the surface at any given instant.

In respiratory physiology, one has gaseous mixtures of oxygen, nitrogen, and carbon dioxide. The rate of diffusion of each of these gases is directly proportional to the pressure caused by that gas alone, which is called the partial pressure of that gas.

Front 98

98. What determines the partial pressure of a gas in a solution?

Back 98

1. Concentration
2. Solubility coefficient of the gas

Henry's law =

partial pressure = (concentration of dissolved gas) / (solubility coefficient)

Front 99

99. Rank order of solubility coefficients at 1 atm

Back 99

1. Carbon dioxide (.57)
2. Oxygen (.024)
3. Carbon monoxide (.018)
4. Nitrogen (.012)
5. Helium (.008)

From this, we can see that carbon dioxide is more than 20x as soluble as oxygen. Therefore, the partial pressure of carbon dioxide for a given concentration is less than 1/20th that exerted by oxygen

Front 100

100. What determines the direction of net diffusion?

Back 100

Net diffusion is determined by the difference between the two partial pressures.

If the partial pressure is greater in the gas phase in the alveoli, as is normally true for oxygen, then more molecules will diffuse into the blood than in the other direction.

Alternatively, if the partial pressure of the gas is greater in the dissolved state in the blood, which is normally true for carbon dioxide, then net diffusion will occur toward the gas phase in the alveoli.

Front 101

101. Vapor pressure

Back 101

The partial pressure that the water molecules exert to escape through the surface is called the vapor pressure of water.

At normal body temp, this vapor pressure is 47 mm Hg.

Front 102

102. What factors affect the rate of diffusion?

Back 102

1. Pressure difference
2. Solubility of the gas in the fluid
3. The cross sectional are of the fluid
4. The distance through which the gas must diffuse
5. The molecular weight of the gas
6. The temperature of the fluid.

Front 103

103. Diffusion rate equation

Back 103

D = [∆P x A x S] / [d x √(MW)]

Where:
D is the diffusion rate
∆P is the partial pressure difference
A is the cross-sectional area
S is the solubility of the gas
d is the distance of diffusion
MW is the molecular weight of the gas

Front 104

104. Diffusion of gases through tissues

Back 104

The gases that are of respiratory importance are all highly soluble in lipids and are highly soluble in cell membranes.

Because of this, the major limitation to the movement of gases in tissues is the rate at which the gases can diffuse through the tissue water instead of through the cell membranes.

Therefore, diffusion of gases through the tissues, including thru the respiratory membrane, is almost equal to the diffusion of gases in water.

Front 105

105. Composition of alveolar air

Back 105

Alveolar air does not have the same concentrations of gases as atmospheric air for the following reasons:

1. The alveolar air is only partially replaced by atmospheric air with each breath
2. Oxygen is constantly being absorbed into the pulmonary blood from the alveolar air.
3. Carbon dioxide is constantly diffusion for the pulmonary blood into the alveoli
4. Dry atmospheric air that enters the respiratory passages is humidified even before it reaches the alveoli.

Front 106

106. What happens as atmospheric air enters the respiratory passages?

Back 106

Atmospheric air is composed of nitrogen and oxygen; almost no water.

As soon as it enters the respiratory passages, it is exposed to the fluids that cover the respiratory surfaces and becomes totally humidified.

*Because the total pressure in the alveoli cannot rise to more than the atmospheric pressure (760 m Hg at sea level), this water vapor simply dilutes all the other gases in the inspired air.

Front 107

107. Rate of alveolar air exchange

Back 107

The volume of alveolar air replaced by new atmospheric air with each breath is only 1/7th of the total, so that multiple breaths are required to exchange most of the alveolar air.

Front 108

108. What is the importance of the slow replacement of alveolar air?

Back 108

Prevents sudden changes in gas concentrations in the blood.

This makes the respiratory control mechanism much more stable than it would be otherwise, and it helps prevent excessive increase and decreases in tissue oxygenation, tissue carbon dioxide concentration, and tissue pH when respiration is temporarily interrupted.

Front 109

109. What affects the oxygen concentration in the alveoli?

Back 109

1. The rate of absorption of oxygen into the blood

2. The rate of entry of new oxygen into the lungs by the ventilatory process

However, the pO2 can never increase above 149 mm Hg as long as the person is breathing normal atmospheric air at sea level pressure, because this is the maximum pO2 in humidified air at this pressure.

Front 110

110. Normal ventilatory rate and consumption of oxygen

Back 110

Normal ventilatory rate: 4.2 L/min

Normal oxygen consumption: 250 mL/min

Front 111

111. Alveolar pCO2

Back 111

The alveolar pCO2 increases directly in proportion to the rate of carbon dioxide excretion

The alveolar pCO2 decreases in inverse proportion to alveolar ventilation

Therefore, the concentrations and partial pressure of both oxygen and carbon dioxide in the alveoli are determined by the rates of absorption or excretion of the two gases and by the amount of alveolar ventilation.

Front 112

112. What makes up expired air?

How does one sample true alveolar air?

Back 112

Amount of expired air is determined by:

1. The amount of expired air that is dead space air

2. The amount of expired air that is alveolar air.

Can sample true alveolar air by collecting the last portion of the expired air after forceful expiration has removed all the dead space air.

Front 113

113. What makes up the "respiratory unit"?

Back 113

1. Respiratory bronchiole
2. Alveolar ducts
3. Atria
4. Alveoli

Front 114

114. Respiratory membrane

Back 114

AKA pulmonary membrane

This is where the gas exchange between the alveolar air and the pulmonary blood occurs.

Front 115

115. What are the layers of the pulmonary membrane?

Back 115

1. Fluid lining the alveolus and containing surfactant that reduces the surface tension of the alveolar fluid
2. Alveolar epithelium composed of thin epithelial cells
3. Epithelial basement membrane
4. Thin interstitial space between the alveolar epithelium and the capillary membrane
5. Capillary basement membrane that in many places fuses with the alveolar epithelial basement membrane
6. Capillary endothelial membrane

Front 116

116. What is the significance of the pulmonary membrane diameter being only 5 micrometers?

Back 116

The RBC must squeeze through them, and the RBC membrane usually touches the capillary wall, so that oxygen and carbon dioxide need not pass through significant amounts of plasma as they diffuse between the alveolus and the red cell.

This increases the rapidity of diffusion.

Front 117

117. What factors determine the rate of gas diffusion across the respiratory membrane?

Back 117

1. Thickness of the membrane
2. Surface area of the membrane
3. Diffusion coefficient of the gas in the substance of the membrane
4. Partial pressure difference of the gas between the two sides of the membrane.

Front 118

118. What can increase the thickness of the respiratory membrane?

Back 118

1. Edema in the interstitial space of the membrane and in the alveoli, so that the respiratory gases must then diffuse not only through the membrane but also through this fluid

2. Some pulmonary diseases also cause fibrosis of the lungs

Front 119

119. What can decrease the surface area of the respiratory membrane?

Back 119

1. Removal of an entire lung (Duh!)

2. Emphysema
-many of the alveoli coalesce, with dissolution of many alveolar walls.

Front 120

120. Diffusing capacity of the respiratory membrane

Back 120

The volume of a gas that will diffuse through the membrane each minute for a partial pressure difference of 1 mm Hg.

Front 121

121. Normal diffusing capacity for oxygen

Back 121

21 mL/min/mm Hg

Total about 230 mL/min

Front 122

122. Change in oxygen diffusing capacity during exercise

Back 122

Increases to a max of 65 mL/min/mm Hg

Increase due to:
1. Opening up of many previously dormant pulmonary capillaries, thereby increasing the surface area of blood into which the oxygen can diffuse

2. A better match between the ventilation of the alveoli and the perfusion of the alveolar capillaries with blood

Therefore, during exercise, oxygenation of the blood is increased not only be increased alveolar ventilation but also by greater diffusing capacity of the respiratory membrane for transporting oxygen into the blood.

Front 123

123. Diffusing capacity for carbon dioxide

Back 123

Has never been measured before b/c it diffuses through the respiratory membrane so rapidly that the average pCO2 in the pulmonary blood is not different from the pCO2 in the alveoli

Regardless, normal diffusing capacity should be: 400-450 mL/min/mm Hg during resting conditions

Front 124

124. Ventilation perfusion ratio

Back 124

Is expressed as Va/Q

When Va (alveolar ventilation) is normal for a given alveolus and Q (blood flow) is also normal for the same alveolus, the ventilation-perfusion ratio is said to be normal.

When Va is zero, yet there is still perfusion (Q), the Va/Q is zero

On the other hand, when there is adequate ventilation (Va), but zero perfusion (Q), the ratio of Va/Q is infinity.

At a ratio of either zero or infinity, there is no exchange of gases through the respiratory membrane of the affected alveoli

Front 125

125. Physiological shunt

Back 125

When Va/Q is below normal

There is inadequate ventilation to provide the oxygen needed to fully oxygenate the blood flowing through the alveolar capillaries.

Therefore, a certain fraction of the venous blood passing thru the pulmonary capillaries does not become oxygenated. This fraction is called shunted blood.

Thus, the greater the physiologic shunt, the greater the amount of blood that fails to be oxygenated as it passed thru the lungs

Front 126

126. Physiological dead space

Back 126

When Va/Q is greater than normal

The ventilation of some of the alveoli is great but alveolar blood flow is low; there is far more available oxygen in the alveoli than can be transported away from the alveoli by the flowing blood.

Thus, the ventilation of these alveoli is said to be wasted.
The ventilation of the anatomical dead space areas is also wasted; it is the sum of these two types of wasted ventilation that is called the physiological dead space.

When the physiologic dead space is great, much of the work of ventilation is wasted effort because so much of the ventilating air never reaches the blood.

Front 127

127. Va/Q in the upper and lower normal lung

Back 127

In a normal person in the upright position, at the top of the lung, Va/Q is as much as 2.5x as great as the ideal value, which causes a moderate degree of physiologic dead space in this area of the lung.

In the bottom of the lung, there is slightly too little ventilation in relation to blood flow, with Va/Q as low as 0.6x the ideal value, representing a physiologic shunt.

However, during exercise, blood flow to the upper part of the lung increases markedly, so that far less physiologic dead space occurs, and the effectiveness of gas exchange now approaches optimum.

Front 128

128. Va/Q in chronic obstructive lung diseases

Back 128

Some areas of the lung exhibit serious physiologic shunt, and other areas exhibit serious physiologic dead space.

Both these conditions tremendously decrease the effectiveness of the lungs as gas exchange organs.

Front 129

129. What is the effect of rate of blood flow on interstitial fluid pO2?

Back 129

If the blood flow thru a particular tissue is increased, greater quantities of oxygen are transported into the tissue, and the tissue pO2 becomes correspondingly higher.

However, the upper limit to which the pO2 can rise, even w/maximal blood flow, is 95 mm Hg, b/c this is the O2 pressure in the arterial blood.

Conversely, if blood flow thru the tissue decreases, the tissue pO2 also decreases.

Front 130

130. What is the effect of rate of tissue metabolism on interstitial fluid pO2?

Back 130

If the cells use more oxygen for metabolism than normally, this reduces the interstitial fluid pO2.

In other words, when the cellular O2 consumption is increased, there is reduced pO2 in the interstitial fluid;

On the other hand, increased pO2 occurs when consumption is decreased.

Front 131

131. Which has a higher pO2 concentration, the peripheral tissue cells or the peripheral capillaries?

Back 131

The peripheral capillaries have a higher pO2 b/c oxygen is always being used by the cells and therefore the intracellular pO2 in the peripheral tissue cells always remains lower.

Front 132

132. What happens when O2 is used by the cells?

Back 132

Virtually all of the O2 becomes carbon dioxide, and this increases the intracellular pCO2; because of this high tissue cell pCO2, carbon dioxide diffuses from the cells into the tissue capillaries and is then carried by the blood to the lungs.

In the lungs, it diffuses from the pulmonary capillaries into the alveoli and is expired.

Front 133

133. CO2 pressures in intracellular vs. interstitial fluids

Back 133

Intracellular pCO2: 46 mm Hg

Interstitial pCO2: 45 mm Hg

Thus, there is only a 1 mm Hg pressure differential

Front 134

134. CO2 pressures in arterial blood vs. venous blood

Back 134

pCO2 in arterial blood: 40 mm Hg

pCO2 in venous blood: 45 mm Hg

Thus, the tissue capillary blood come almost exactly to equilibrium w/the interstitial pCO2 of 45 mm Hg.

Front 135

135. CO2 pressures in blood entering pulmonary capillaries at arterial end vs. in the alveolar air

Back 135

pCO2 in blood entering pulmonary capillaries at arterial end: 45 mm Hg

pCO2 of the alveolar air: 40 mm Hg

Thus, only a 5 mm Hg pressure difference causes all the required carbon dioxide diffusion out of the pulmonary capillaries into the alveoli.

Front 136

136. What is the effect of tissue metabolism and tissue blood flow on interstitial pCO2?

Back 136

Tissue capillary blood flow and tissue metabolism affect the pCO2 in ways exactly opposite to their effect on tissue pO2

A decrease in blood flow from normal increases peripheral tissue pCO2; an increase in blood flow decreases the interstitial pCO2

Also, an increase in tissue metabolic rate greatly elevates the interstitial fluid pCO2, whereas decreasing the metabolism causes the interstitial pCO2 to fall.

Front 137

137. What is the role of hemoglobin in O2 transport?

Back 137

Under normal conditions, oxygen is carried to the tissues almost entirely by hemoglobin (97%)

The rest is transported in the dissolved state in the water of the plasma and blood cells.

Front 138

138. Explain the nature of the reversible combination of oxygen with hemoglobin

Back 138

Oxygen binds loosely and reversibly with the heme portion of hemoglobin molecules.

When pO2 is high, as in the pulmonary capillaries, oxygen binds w/the hemoglobin

When pO2 is low, as in the tissue capillaries, oxygen is released from the hemoglobin

Front 139

139. What is the usual oxygen saturation of systemic arterial blood?

Back 139

97%

Front 140

140. What is the saturation of hemoglobin in normal venous blood?

Back 140

Averages 75%

Front 141

141. What is the maximum amount of oxygen that can combine with the hemoglobin of blood?

Back 141

The blood of a normal person contains about 15 grams of hemoglobin in each 100 mL of blood, and each gram of hemoglobin can bind with a maximum of 1.34 mL of oxygen.

Therefore 15 x 1.35 = 20.1, which means that on average, 15 g of hemoglobin can combine with a total of almost exactly 20 mL of O2 if the Hb is 100% saturated.

This is usually expressed as 20 volumes per cent.

Front 142

142. Amount of oxygen released form the Hb when systemic arterial blood flows thru the tissues

Back 142

The total quantity of O2 bound with Hb in normal systemic arterial blood, which is about 97% saturated, is 19.4 mL per 100 mL of blood.

On passing thru the tissue capillaries, this amount is reduced, on average, to 14.4 mL.

Thus, under normal conditions, about 5 mL of O2 are transported form the lungs to the tissues by each 100 mL of blood.

Front 143

143. Utilization coefficient

Back 143

The percentage of the blood that gives up its oxygen as it passes thru the tissue capillaries is called the utilization coefficient.

The normal value for this is about 25%, that is, 25% of the oxgenated Hb gives its oxygen to the tissues.

During exercise, the utilization coefficient can increase to 75 to 85%.

Front 144

144. Role of hemoglobin as a buffer for tissue pO2

Back 144

Hemoglobin in the blood is mainly responsible for stabilizing the oxygen pressure in the tissues.

During heavy exercise, extra amounts of oxygen must be delivered from the Hb to the tissues. But this can be achieved with little further decrease in tissue pO2 because:

1. The steep slope of the dissociation curve
2. The increase in tissue blood flow caused by the decreased pO2; that is, a very small fall in pO2 causes large amount of extra oxygen to be released from the Hb.

Thus, the hemoglobin in the blood automatically delivers oxygen to the tissues at a pressure that is held rather tightly between about 15 and 40 mm Hg

Front 145

145. Factors that shift the oxygen-hemoglobin dissociation curve to the left

Back 145

1. ↑ pH

2. ↓ CO2

3. ↓ Temperature

4. ↓ BPG

Front 146

146. Factors that shift the oxygen-hemoglobin dissociation curve to the right

Back 146

1. ↓ pH

2. ↑ CO2

3. ↑ Temperature

4. ↑ BPG

Front 147

147. The Bohr effect

Back 147

A shift of the oxygen-Hb dissociation curve to the right in response to increases in blood carbon dioxide and hydrogen ions has a significant effect by enhancing the release of oxygen from the blood in the tissues and enhancing oxygenation of the blood in the lungs.

As the blood passes thru the tissues, carbon dioxide diffuses from the tissue cells into the blood. This increases the blood pO2 which in turn raises the blood H2CO3 (carbonic acid) and the H+ concentration.

These effects shift the O2-Hb dissociation curve to the right and downward, forcing oxygen away from the hemoglobin and therefore delivering increased amount of O2 to the tissues.

Exactly the opposite effects occur in the lungs

Front 148

148. Effect of BPG on the O2-Hb dissociation curve

Back 148

The normal BPG in the blood keeps the O2-Hb dissociation curve shifted slightly to the right all the time.

In hypoxic conditions, the quantity of BPG in the blood increases considerably and shifts the curve even farther to the right.

Front 149

149. Shift of the dissociation curve during exercise

Back 149

During exercise, the curve shifts considerably to the right, thus delivering extra amounts of O2 to the active, exercising muscle fibers.

The muscles release larger quantities of carbon dioxide and server other acids which increase the H+ concentration.

In addition, increased temp of the muscles increases O2 delivery even more.

All there factors act together to shift the curve or the muscle capillary blood to the right.

Again, in the lungs, the shift occurs in the opposite direction, allowing the pickup of extra amounts of oxygen from the alveoli.

Front 150

150. Effect of intracellular pO2 on rate of oxygen usage

Back 150

Only a minute level of O2 pressure is required in the cells for normal intracellular chemical reactions to take place.

The respiratory enzymes in the cells are geared so that when the cellular pO2 is more than 1 mm Hg, oxygen availability is no longer a limiting factor in the rates of chemical reactions.

Instead, the main limiting factor is the concentration of ADP in the cells.

When the concentration of ADP is altered, the rate of oxygen usage changes in proportion to the change in ADP concentration.

Front 151

151. Under normal conditions, what ultimately controls the rate of oxygen usage by the cells?

Back 151

The rate of energy expenditure within the cells - that is, by the rate at which ADP is formed from ATP.

Front 152

152. Effect of diffusion distance from the capillary to the cell on oxygen usage

Back 152

Tissue cells are seldom more than 50 um away from the capillary, and oxygen normally can diffuse readily enough from the capillary to the cell to supply all the required amounts of oxygen for metabolism.

However, occasionally, cells are located farther from the capillaries, and the rate of oxygen diffusion to these cells can become so low that intracellular pO2 falls below the critical level required to maintain maximal intracellular metabolism.

Front 153

153. What is the effect of blood flow on metabolic use of oxygen?

Back 153

The total amount of oxygen available each minute for use in any given tissue is determined by:

1. The quantity of oxygen that can be transported to the tissue in each 100 mL of blood

2. The rate of blood flow

If the rate of blood flow falls to zero, the amount of available oxygen also falls to zero.

There are times when the rote can be so low that tissue pO2 falls below the critical 1 mm Hg required for intracellular metabolism.

Under these conditions, the rate of the tissue usage of O2 is blood flow limited.

Front 154

154. Carbon monoxide and Hb

Back 154

CO binds with Hb at the same point on the Hb molecule as does oxygen; it can therefore displace oxygen from the Hb, thereby decreasing the oxygen carrying capacity of blood.

Further, it binds with about 250x as much tenacity as oxygen.

The CO-Hb dissociation curve is identical to the O2-Hb dissociation curve; however, the CO pressures are at a level 1/250 of those for oxygen.

A pCO of only 0.6 mm Hg can be lethal

Front 155

155. What are the signs of CO poisoning?

Back 155

Even though the oxygen content of blood is greatly reduced in CO poisoning, the pO2 of the blood may be normal. This makes exposure to carbon monoxide esp dangerous, b/c the blood is bright red and there are no obvious signs of hypoxia (cyanosis).

Also, pO2 is not reduced, and the feedback mechanism that usually stimulates increased respiration rate in hypoxic situations is absent.

Thus, a person may become disoriented and unconscious before becoming aware of the danger.

Front 156

156. Treatment for CO poisoning

Back 156

Can be treated by administering pure oxygen, because oxygen at high alveolar pressure can displace carbon monoxide rapidly from its combination with Hb.

The patient can also benefit from simultaneous admin of 5% carbon dioxide, because this strongly stimulates the respiratory center which increases alveolar ventilation and reduces that alveolar carbon monoxide.

Front 157

157. What is the average amount of carbon dioxide that is transported from the tissues to the lungs in each 100 mL of blood?

Back 157

Under normal resting conditions, an average of 4 mL of carbon dioxide is transported from the tissues to the lungs in each 100 mL of blood

Front 158

158. Transport of carbon dioxide in the dissolved state

Back 158

A small portion of the carbon dioxide (7%) is transported in the dissolved state to the lungs

When dissolved in the blood, the carbon dioxide reacts with water to for carbonic acid via carbonic anhydrase, which catalyzes the reaction. This reaction is rapid and allows tremendous amts of CO2 to react with the RBC water even before the blood leaves the tissue capillaries

Front 159

159. Dissociation of carbonic acid into bicarbonate and hydrogen ions

Back 159

In another fraction of a second, the carbonic acid dissociates into hydrogen and bicarbonate ions.

Most of the H+ ions then combine with the Hb in the RBCs, because the Hb protein is a powerful acid-base buffer.

Front 160

160. Chloride shift

Back 160

Many bicarbonate ions then diffuse into the red cells to take their place.

This is made possible by the presence of a special bicarbonate-chloride carrier protein in the RBC membrane that shuttles these two ions in opposite directions at rapid velocities.

Thus, the chloride content of venous RBCs is greater than that of arterial red cells, a phenomenon called the "chloride shift"

Front 161

161. Acetazolamide

Back 161

A carbonic anhydrase inhibitor that is administered to an animal to block the action of carbonic anhydrase in the RBCs.

Carbon dioxide transport from the tissues becomes so poor that the tissue pCO2 can be made to rise to 80 mm Hg instead of the normal 45 mm Hg

Front 162

162. Transport of carbon dioxide in combo with Hb and plasma proteins

Back 162

In addition to reacting with water, carbon dioxide reacts directly with amine radicals of the Hb molecule to for the compound carbaminohemoglobin.

This combination is a reversible reaction that occurs with a loose bond, so that the carbon dioxide is easily released into the alveoli, where the pCO2 is lower than in the pulmonary capillaries.

A small amt of carbon dioxide also reacts in the same way with the plasma proteins in the tissue capillaries.

About 30% (actual no more than 20%) of the total CO2 transported is by combination with Hb and plasma proteins.

Front 163

163. Carbon dioxide dissociation curve

Back 163

Dependent on total blood carbon dioxide in all its forms on pCO2.

Normal range of blood pCO2 is between 40 mm Hg in arterial blood and 45 mm Hg in venous blood.

Front 164

164. Haldane effect

Back 164

Binding of oxygen with hemoglobin tends to displace carbon dioxide from the blood.

Essentially, it approximately doubles the amount of carbon dioxide released from the blood in the lungs and approximately doubles the pickup of carbon dioxide in the tissues.

This effect, called the Haldane effect, is quantitatively more important in promoting carbon dioxide transport than is the Bohr effect in promoting oxygen transport.

Front 165

165. What causes the Haldane effect?

Back 165

Results from the simple fact that the combo of oxygen with Hb in the lungs causes the Hb to become a stronger acid. This displaces the CO2 from the blood and the alveoli in two ways:

1. The more highly acidic Hb has less tendency to combine with CO2 to for carbaminohemoglobin, thus displacing much of the CO2 that is present in the carbamino form from the blood.
2. The increased acidity of the Hb also causes it to release an excess of H+ ions, and these bind with bicarbonate ions to form carbonic acid; this then dissociates into water and CO2, and the CO2 is released from the blood into the alveoli, and finally, into the air.

Front 166

166. Change in blood acidity during carbon dioxide transport

Back 166

The carbonic acid formed when carbon dioxide enters the blood in the peripheral tissues decreases the blood pH.

However, due to buffering, this decrease is minimal; going from 7.41 to 7.37.

The reverse occurs when CO2 is released from the blood in the lungs, with the pH rising to the arterial value of 7.41 once again.

Front 167

167. Normal transport of oxygen from the lungs to the tissues vs. normal transport of carbon dioxide from the tissues to the lungs

Back 167

The normal transport of oxygen from the lungs to the tissues by each 100 mL of blood is about 5 mL, whereas normal transport of carbon dioxide from the tissues to the lungs is about 4 mL.

Front 168

168. Respiratory exchange ratio

Back 168

The ratio of carbon dioxide output to oxygen uptake is called the respiratory exchange ratio (R).

R = (Rate of CO2 output) / (Rate of oxygen uptake)

Under normal resting conditions, R = 0.82

The value for R changes under different metabolic conditions.

Front 169

169. When does R = 1.00?

Back 169

When a person is using exclusively carbohydrates for body metabolism

Front 170

170. When does R = 0.7?

Back 170

When the person is using exclusively fats for metabolic energy

Front 171

171. Why the difference in R values when using fats vs. carbs for energy?

Back 171

When oxygen is metabolized with carbs, one molecule of CO2 is formed for each molecule of oxygen consumed

When oxygen reacts with fats, a large share of the oxygen combines with hydrogen atoms from the fats to form water instead of CO2.

For a person on a normal diet, consuming avg amts of carbs, fats, and proteins, R = 0.825

Front 172

172. Roles of plasma proteins

Back 172

1. Maintaining proper distribution of water between blood and tissues

2. Transporting nutrients, metabolites, and hormones throughout the body

3. Defending against infection

4. Maintaining the integrity of circulation through clotting

Front 173

173. Body fluid maintenance at arteriolar end of capillaries

Back 173

The hydrostatic pressure in the arteriolar end of the capillaries (~37 mm Hg) exceeds the sum of the tissue pressure (~1 mm Hg).

Thus, water tends to leave the capillaries and enter extravascular spaces.

Front 174

174. Body fluid maintenance at venous end of capillaries

Back 174

The hydrostatic pressure falls to approx 17 mm Hg while the osmotic pressure and the tissue pressure remain constant, resulting in movement of fluid back from the extravascular (interstitial) spaces and into the blood.

Thus, most of the force bringing water back from the tissues into the plasma is the osmotic pressure mediated by the presence of proteins in the plasma.

Front 175

175. Albumin

Back 175

Major protein synthesized by the liver; which constitutes approx 60% of the total plasma protein, but b/c of its small size, it is thought to contribute to 70 to 80% of the total osmotic pressure of the plasma.

Front 176

176. Composition of albumin

Back 176

Albumin is a glycoprotein and is a carrier of free fatty acids, calcium, zinc, steroid hormones, copper, and bilirubin.

Many drugs also bind to albumin, which can have phamacological implications.

For instance, when a drug binds to albumin, it will lower the effective concentration of that drug and may lengthen its lifetime in the circulation.

Front 177

177. Two different sets of plasma proteins that aid in the immune response

Back 177

1. Immunoglobulins

2. Complement proteins

Front 178

178. Immunoglobulins

Back 178

Secreted by a subset of differentiated B-lymphocytes termed plasma cells and bind antigens at binding sites.

Once the antibody-antigen complex is formed, it must be cleared from the circulation. The complement system participates in this function.

Front 179

179. Complement proteins

Back 179

Consists of approx 20 proteins becoming activated by triggers and then results in a proteolytic activation cascade of the proteins.

This results in the release of biologically active peptides or polypeptide fragments.

These peptides mediate the inflammatory response, attract phagocytic cells, initiate degranulation of granulocytes, and promote clearance of antigen-antibody complexes.

Front 180

180. Protease inhibitors in plasma

Back 180

Serve to carefully control the inflammatory response.

Activated neutrophils release lysosomal proteases from their granules that can attack elastin, the various types of collagen, and other ECM proteins.

However, the product of neutrophil myeloperoxidase, HOCl, inactivates the protease inhibitors, thereby ensuring that the proteases are active at the site of infection.

Front 181

181. How do plasma proteins maintain the integrity of the circulatory system?

Back 181

When blood is lost from the circulation due to vessel wall damage, the subendothelial cell layer is exposed.

In response to the damage, a barrier (the hemostatic plug, a fibrin clot), initiated by platelet binding to the damaged area, is formed at the site of injury.

Regulatory mechanisms limit clot formation to the site of injury and control its size and stability.

As the vessel heals, the clot is degraded (fibrinolysis). Plasma proteins are required for these processes to occur.

Front 182

182. Platelets

Back 182

Non-nucleated cells in the blood whose major role is to form mechanical plugs at the site of vessel injury and to secrete regulators of the clotting process and vascular repair.

Derived from megakaryocytes in the bone marrow; a single megakaryocyte gives rise to 4,000 platelets

Front 183

183. Structure of non-activated platelets

Back 183

A nonactivated platelet has a plasma membrane that invaginates extensively into the interior of the cell, forming an open membrane system. B/c the plasma membrane contains receptors and phospholipids that accelerator the clotting process, the open membrane system increases the membrane surface area that is potentially available for clotting reactions.

The interior contains microfilaments and an extensive actin/myosin system.

Front 184

184. Structure of activated platelets

Back 184

In response to endothelial injury, platelet activation causes calcium dependent changes int eh contractile elements, which, in turn, substantially change the architecture of the plasma membrane.

Long pseudopodia are generated, increasing the surface area of the membrane as clot formation is initiated.

Front 185

185. Three types of granules present in platelets

Back 185

1. Electron-dense granules that contain calcium, ADP, ATP, and serotonin

2. α-granules, which contain a heparin antagonist, platelet derived growth factor, β-thromboglobulin, fibrinogen, vWF, and other clotting factors

3. Lysosomal granules, which contain hydrolytic enzymes.

During activation, the contents of these granules, which modulate platelet aggregation and clotting, are secreted.

Front 186

186. Three fundamental mechanism involved in platelet function during blood coagulation

Back 186

1. Adhesion
2. Aggregation
3. Secretion

Adhesion sets off a series of reactions termed platelet activation, which leads to platelet aggregation and secretion of the platelet granule contents.

Front 187

187. Platelet adhesion

Back 187

Refers primarily to the platelet-subendothelial interaction that occurs when platelets intially adhere to the sites of blood vessel injury.

Blood vessel injury exposes collagen, vWF, and other matrix components.

The platelet cell membrane contains glycoproteins that bind to collagen and to vWF, causing the platelet to adhere to the subendothelium.

Binding to collage by GPIa causes the platelet to change its shape from a flat disc to a spherical cell which promotes platelet/platelet interactions.

Binding of the subendothelial vWF by GPIb causes changes in the platelet membrane that expose GPIIb/IIIa binding sites to fibrinogen and vWF

Front 188

188. vWF

Back 188

von Willebrand factor

Is a large multimeric glycoprotein synthesized in endothelial cells and megakaryocytes, and is located in the subendothelial matrix, in specific granules, and in the circulation bound to Factor 8.

Its role is to stabilize Factor 8 and protect it from degradation

Front 189

189. What happens after the initial adherence of platelets?

Back 189

Sets off a series of reactions that results in in more platelets being recruited and aggregated at the site of injury.

1. Some platelets release the contents of their dense granules and their α-granules, with ADP release
2. ADP released from platelets binds to a receptor on the platelet membrane, which leads to further unmasking of GPIIb/IIIa binding sites.
3. Binding of fibrinogen

*Aggregation of platelets cannot take place without ADP stimulation, because ADP induces swelling of the activated platelets, promoting platelet/platelet contact and adherence

Front 190

190. Fibrinogen

Back 190

Protein that circulates in the blood and is also found in platelet granules.

It consists of two triple helices held together with disulfide bonds.

Binding of fibrinogen to activated platelets is necessary for aggregation, providing, in part, the mechanism by which platelets adhere to one another.

Front 191

191. Soft clots and thrombin

Back 191

Cleavage of fibrinogen by thrombin produces fibrin monomers that polymerize and, together with platelets, form a "soft clot".

Thrombin itself is a potent activator of platelets, through binding to a specific receptor on the platelet surface.

Front 192

192. Serine protease proenzymes

Back 192

1. Factor 7
2. Factor 9
3. Factor 10
4. Factor 11

When these factors are activated by cleavage, they cleave the next proenzyme in the cascade.

Front 193

193. Cofactor proteins

Back 193

1. Tissue factor
2. Factor 5
3. Factor 8


Serve as binding sites for other factors on the platelet surface, thereby accelerating and localizing the reactions

Front 194

194. Proteins S and C

Back 194

Considered part of the blood coagulation cascade and are regulatory proteins.

Only protein C is regulated by proteolytic cleavage, and when it is activated, it is itself a serine protease.

Front 195

195. Vasoconstrictors released from platelets

Back 195

Serotonin released from the dense granules of the platelets and the synthesis of thromboxane A2 is stimulated

This reduces blood flow to the damaged area.

Also, platelet derived growth factor, which stimulates proliferation of vascular cells, is also released into the environment surrounding the damage

Front 196

196. Formation of thrombin

Back 196

The result of the common cascade is thrombin formation, which augments its own formation by converting Factors 5, 8, and 11 into activated cofactors and stimulating platelet degranulation.

Front 197

197. Activation of prothrombin

Back 197

Initially, activation is slow b/c the activator cofactors, 8a, and 5a, are present only in small amounts.

However, once a small amount of thrombin is activated, it accelerates its own production by cleaving factors 5 and 8 to their active forms.

Front 198

198. Cross-linking of fibrin

Back 198

Factor 13a catalyzes a transamidation reaction between Gln and Lys side chains on adjacent fibrin monomers.

The covalent cross-linking takes place in 3D, creating a strong network of fibers that is resistant to mechanical and proteolytic damage.

This network of fibrin fibers traps the aggregated platelets and other cells, forming the clot that plugs the vent in the vascular wall.

Front 199

199. Two important consequences of complex assembly on the surface of activated platelets

Back 199

1. Enhances the rate of thrombin formation by as much as several hundred thousand fold, enabling the clot to form rapidly enough to preserve hemostasis

2. Such explosive thrombin formation is localized to the site of vascular injury at which the negatively charged phospholipids are exposed (exposed phopsholipids must mean substantial cell damage must have occurred).

Front 200

200. Vitamin K requirement for blood coagulation

Back 200

The formation of γ-carboxyglutamate residues on blood coagulation factors (Factors 2, 7, 9, 10, proteins C and S) takes place in the hepatocyte before release of the protein.

Within the hepatocyte, vitamin K is reduced to form vitamin KH2 by a microsomal quinone reductase.

Vitamin KH2 is a cofactor for the carboxylases that add a carboxyl group to the appropriate glutamate residues in the proenzyme to form the carboxylated proenzyme (i.e. prothrombin).

In the same reaction, vitamin K is converted to vitamin K epoxide.

To recover active vitamin KH2, vitamin K is first reduced to the quinone form by vitamin K epoxide reductase, and then to the active hydroquinone form.

Front 201

201. Role of thrombin in clot regulation

Back 201

Thrombin has a prothrombotic and an antithrombotic role.

The prothrombotic action is initiated when thrombin stimulates its own formation by activating Factors 5, 8, and 11. It also promotes clot formation by activating platelet aggregation.

Antithrombotic effects of thrombin result from its binding to an endothelial receptor called thrombomodulin. Thrombomodulin abolishes the clotting function of thrombin and allows thrombin to activate protein C, which has anticoagulant effects.

Front 202

202. Proteins S and C (take two)

Back 202

Serve to suppress the activity of the coagulation cascade.

After activation, protein C forms a complex with protein S. Protein S anchors the activated protein C complex (APC) to the clot through calcium/γ-carboyxglutamate binding to platelet phospholipids.

The APC destroys the active blood coagulation cofactors Factors 8a and 5a by proteolytic cleavage, decreasing the production of thrombin.

The APC also stimulates endothelial cells to increase secretion of the prostaglandin PGI2, which reduces platelet aggregation

Front 203

203. Serpins

Back 203

SERine Protease INhibitors

A group of naturally occurring inhibitory proteins that are present in the plasma at high concentration.

Each inhibitor possesses a reactive site that appears to be an ideal substrate for a specific serine protease and thus acts as a trap for that protease.

The bound serine protease attacks a peptide bond located at a critical amino acid residue within the serpin and forms a tight enzyme-inhibitor complex.

Front 204

204. Antithrombin III (ATIII)

Back 204

A serpin that controls the activity of thrombin.

One molecule of ATIII irreversibly inactivates one molecule of thrombin thru reaction of an arginine residue in ATIII with the active-site serine residue of thrombin.

ATIII-thrombin complex formation is markedly enhanced in the presence of heparin.

Front 205

205. ATIII and heparin

Back 205

Heparin binds to lysyl residues on ATIII and dramatically accelerates its rate of position of the critical arginine residues on ATIII and dramatically accelerates its rate of binding to thrombin.

This is b/c of an allosteric alteration in ATIII such that the position of the critical arginine residue of ATIII is more readily available for interaction with thrombin.

The formation of the ATIII-thrombin complex releases the heparin molecule so that it can be re-used as a catalyst.

Front 206

206. Thromboresistance of normal vascular endothelium

Back 206

Contributed to by several properties:

1. Endothelial cells are highly negatively charged, a feature that may repel the negatively charge platelets.

2. Endothelial cells synthesize prostaglandin I2 (PGI2), NO, vasodilators and powerful inhibitors of platelet aggregation

3. Endothelial cells also synthesize two cofactors that each inhibit the action of thrombin, thrombomodulin, and heparan sulfate.

Front 207

207. Fibrinolysis

Back 207

After successful formation of a hemostatic plug, further propagation of the clot must be prevented. This is accomplished in part by switching off blood coagulation and in part by turning on fibrinolysis.

This involves the degradation of fibrin in a clot by plasmin, a serine protease that is formed from its zymogen, plasminogen.

Front 208

208. Plasminogen

Back 208

A circulating serum protein that has a high affinity for fibrin, promoting the incorporation of plasminogen in the developing clot.

The inactivity of plasminogen is mediated by proteins known as plasminogen activators.

Front 209

209. Plasminogen activators

Back 209

Work most efficiently at the clot surface. Activated protein C also stimulates the release of plasminogen activators.

Leads to plasmin formation in the circulation, but must bind to fibrin in order to facilitate its activation by protecting it from blood serpins, and by localizing it on the fibrin substrate for subsequent efficient proteolytic attack.

This mechanism allows for dissolution of fibrin in pathologic thrombi or oversized hemostatic plugs, and at the same time prevents degradation of fibrinogen in the circulating blood.

Front 210

210. Two important endogenous plasminogen activators

Back 210

1. t-PA
2. scu-PA

Front 211

211. t-PA

Back 211

Tissue plasminogen activator; produced chiefly by the vascular endothelial cells, has a high binding affinity for fibrin, and plays a major role in fibrinolysis.

Front 212

212. scu-PA

Back 212

Single chain urokinase is synthesized in most cells and tissues and has a moderate affinity for fibrin.

Front 213

213. Streptokinase

Back 213

A bacterial exogenous plasminogen activator from beta-hemolytic streptococci, and is not an enzyme but an allosteric modifier of human plasminogen that allows an autocatalytic reaction such that plasmin is formed.

Front 214

214. Two basic assays for measuring the activity of Factor 8 in a blood sample

Back 214

1. Functional clotting assay
2. Coupled enzyme system leading to the cleavage of a chromogenic substrate, generating a colored product.

Front 215

215. Functional clotting assay

Back 215

A sample of the patient's plasma is added to a Factor 8 deficient sample of plasma and the time to generate clot formation is determined.

Although clot formation is the end product of this assay, one is measuring the eventual activation of Factor 2 to 2a, which allows clot formation to initiate.

Front 216

216. Automated, chromogenic assay

Back 216

A sample of the unknown is mixed with purified Factor 9a, calcium ions, phospholipid vesicles, the chromogenic substrate, and purified Factor 10.

If the unknown sample contains Factor 8, the Factors 8 and 9a will synergize and activate Factor 10 to 10a.

The Factor 10a will cleave the chromogenic substrate, forming a colored product, whose concentration can be determined spectrophotometrically.

Comparison to a standard curve of Factor 8 addition enables an accurate estimate of the level of active Factor 8 in the sample.

Front 217

217. Kwashiorkor

Back 217

Severe protein malnutrition.

The concentration of the plasma proteins decreases, as a result of which the osmotic pressure of the blood decreases.

As a result, fluid is not drawn back to the blood and instead accumulates in the interstitial space (edema).

The distended bellies of famine victims are the result of fluid accumulation in the extravascular tissues because of the severely decreased concentration of plasma proteins, particularly albumin.

Albumin synthesis decreases fairly early under conditions of protein malnutrition.

Front 218

218. Why do individuals with analbuminemia have only moderate edema?

Back 218

Apparently, the concentration of other plasma proteins is increased to compensate for the lack of albumin.

The frequency of analbuminemia is less than one per million individuals.

Front 219

219. α1-Antiproteinase (AAP)

Back 219

The main serine protease inhibitor of human plasma. Individuals with a point mutation in exon 5 of the AAP gene, which results in a single AA substitution in the protein, have diminished secretion of AAP from the liver.

These individuals are at increased risk for developing emphysema.

Insufficient levels of AAP can lead to lack of neutralization nof the elastase and other proteases released. The excess proteolytic activity damages lung tissue, leading to loss of alveolar elasticity and emphysema.

Front 220

220. Bernard-Soulier syndrome

Back 220

Defects in GPIb cause a bleeding disorder known as Bernard-Soulier syndrome.

Platelet aggregation is affected, b/c of the inability of GPIb to adhere to subendothelial vWF

Front 221

221. Deficiency in the amount of functionality of protein C or protein S increases the risk for what?

Back 221

Venous thromboembolism.

Individuals who are homozygous for these mutations do not survive the neonatal period unless they are given replacement therapy.

Front 222

222. Factor V Leiden

Back 222

Present in European populations, a point mutation in the Factor 5 gene causes the replacement of an Arg w/ a Gln in the preferred site for cleavage by activated protein C, rendering Factor 5a Leiden resistant to APC.

Heterozygous individuals have a 6 - 8x increased risk of deep vein thromboses, and homozygous individuals have a 30-140x increased risk.

Inherited APC resistance is the most prevalent risk factor for familial thrombotic disease.

Front 223

223. Hemophilia A

Back 223

Transmitted via X linked

Deficiency in Factor 8, an essential factor required for thrombin activation

Results in an inability to directly activate Factor 10.

Front 224

224. Hemophilia B

Back 224

Caused by mutations in the gene for Factor 9.

Results in an inability to directly activate Factor 9.

Lack of Factor 9 activity leads to an inability to convert prothrombin to thrombin, and impaired clotting.

Front 225

225. Method of vWF activation

Back 225

Mediates platelet adhesion to subendothelium by binding to glycoprotein GPIb and the platelet membrane and by binding to exposed subendothelial collagen.

Front 226

226. Fibrinogen role in platelet aggregation

Back 226

Cross links platelets to one another by binding to GPIIb/IIIa receptors on platelet membranes.

Front 227

227. Role of thromboxane A2

Back 227

Activates platelets thru the activation of G protein in platelet membrane which then activates the cleavage of PIP2 to DAG and IP3 stimulating calcium release

Front 228

228. Cyclooxgenase

Back 228

Converts arachnidonic acid to thromboxane A2

Front 229

229. PLC (Platelet activation)

Back 229

AKA Protein lipase C

Activated by G protein; hydrolyzes PIP2 to yield IP3 and DAG, stimulating further mechanisms of platelet activation.

Front 230

230. IP3 and platelet activation

Back 230

Increases cytosolic calcium concentration needed for the activation of phospholipase A2

Front 231

231. DAG

Back 231

Diacylglycerol

Activates protein kinase C and platelet activation

Front 232

232. Protein kinase C

Back 232

Activates phospholipase A2 in accordance w/increased calcium concentration

Front 233

233. Phospholipase A2

Back 233

Activates membrane protein GPIIb/IIIa

Allows binding of fibrinogen to aggregate platelets.

Front 234

234. ADP activation of platelets

Back 234

1. Activates P2Y G protein receptor to cause an overall increase of cAMP that activates PKA

2. Activates P2Y1 receptor to cause an overall increase in PLC activity in the platelet.

Front 235

235. Fibrous collagen activation of platelets

Back 235

Binds directly to platelet glycoprotein 6

Ligation of glycoprotein 6 by collagen activates phospholipase C

Front 236

236. Prostacyclin (PGI2)

Back 236

An eicosanoid synthesized and secreted by endothelium

Acts thru G proteins to increase cAMP levels within platelets and inhibits platelet granule release and aggregation

Also causes vasodilation due to increase of cAMP levels in smooth muscle cells.

Front 237

237. Protein C & S

Back 237

Vitamin K dependent; inactivates coagulation factors 5a and 8a.

Feedback control in which excess thrombin generation leads to activation of protein C which helps prevent a large fibrin clot from occluding the vascular lumen.

Front 238

238. Tissue factor pathway inhibitor

Back 238

Limits action of tissue factor which initiates the extrinsic coagulation cascade.

Binds to Factor 10a and neutralizes its activity; subsequently the TFPI-10a complex interacts w/ TF-7a complex with a complex forming the quaternary 10a-TFPI-7a-TF complex.

This inactivates the TF-7a complex.

Front 239

239. Alpha-2-antiplasmin

Back 239

Plasma protein that neutralizes free plasmin in circulation and thereby prevents random degradation of plasma fibrinogen.

Front 240

240. Virchow's triad

Back 240

The influence of endothelial injury, abnormal blood flow, and hypercoagulability on one another eventually causes thrombus.

Front 241

241. Turbulent blood flow vs. laminar flow

Back 241

Turbulent blood flow causes endothelial injury, forms countercurrents and forms local pockets of stasis.

Local stasis can also result from formation of an aneurysm and from MI.

Promotes thrombus by three mechanisms:
1. Allows platelets to come into close proximity w/vessel wall
2. Inhibits flow of fresh blood into vascular blood so activated coagulation factors in region are not removed.
3. Promotes endothelial cell activation which leads to prothrombic site.

Front 242

242. Prothrombin G20210a mutation

Back 242

Adenine is substituted for guanine in 3' on translated region of prothrombin gene

Leads to 30% increase in plasma prothrombin levels.

Front 243

243. Heparin induced thrombocytopaenia

Back 243

Stimulates the immune system to generate circulating antibodies directed against a platelet Factor 4-Heparin complex.

B/c platelet Factor 4 is present on platelet surfaces and endothelial surfaces, when bound to the antibody, it causes coagulation via mediation by removal of platelets from the blood.

In some patients, however, antibody platelet binding causes platelet activation, endothelial injury and prothrombotic state.

LMW heparin has a lower incidence of thrombocytopaenia compared to unfractionated heparin

Front 244

244. Aspirin

Back 244

Inhibits synthesis of prostaglandins, thereby inhibiting platelet release reaction and interfering w/normal platelet aggregation.

Aspirin acts by covalently acetylating a serine residue near the active site of the COX enzyme, inhibiting synthesis of cyclic endoperoxide and its various metabolites which are needed to activate Thromboxane A2.

Front 245

245. Aspirin "poisoning" of individual platelets (not of the human (for Denise))

Back 245

Platelets do no contain DNA or RNA so they cannot regenerate new COX enzyme once the aspirin has permanently deactivated the COX enzyme.

Therefor, the platelets are irreversible poisoned for their lifetime (7-10 days)

Inhibition of COX in endothelial cells, on the other hand is not permanent because they do have DNA and RNA

Front 246

246. Aspirin in high doses

Back 246

Can inhibit prostacyclin production w/o increasing effectiveness of the drug as an antiplatelet agent.

Compared to aspirin, other NSAIDs are not as widely used b/c the inhibitory action of these drugs on COX is not permanent.

Front 247

247. Use of selective COX-2 inhibitors

Back 247

Can not be used as antiplatelet agents because they are poor inhibitors of COX-1.

COX-1 is the predominate COX isoform in platelets

COX-2 inhibits are associated w/increased cardiovascular risk likely b/c they inhibit endothelial production of PGI2 w/o inhibiting platelet generation of thromboxane A2

Front 248

248. Phosphodiesterase inhibitors

Back 248

Increase in cellular concentration of cAMP leads to decreased coagulability.

Platelet cAMP levels are regulated by Thromboxane A2 and PGI2

Phosphodiesterase inhibitors inhibit cellular cAMP degradation while activators of platelet adenyl-cyclase decrease platelet aggregation by increasing cAMP. (Dipyridamole is example of this)

Front 249

249. Dipyridamole

Back 249

Phosphodiesterase inhibitor has only weak antiplatelet effects by itself and is usually administered w/warfarin or aspirin

Dipryidamole + warfarin inhibits thrombus formation on prostatic heart valves

Combined w/aspirin can be used to reduce likelihood of thrombosis in patients w/ a thrombotic diathesis.

Also has vasodilatory properties.

May cause angina in patients w/CAD by causing coronary steal syndrome.

Front 250

250. ADP receptor pathway inhibitors

Back 250

1. Ticlopidine
2. Clopidogrel

Irreversibly inhibits ADP receptor pathway of platelet activation and have antiplatelet effects in vitro and in vivo.

Thought to act by covalently modifying and activating platelet P2Y receptor

Front 251

251. Ticlopidine

Back 251

Prodrug that requires conversion to active thiol metabolites in the liver

Max platelet inhibition observed 8-11 days into therapy but time can be reduced by combining it w/aspirin.

Approved for 2ndary prevention of thrombotic strokes in patients intolerant of aspirin

In combo w/aspirin to prevent stent thrombosis

Considered more dangerous than clopidogrel; occasionally associated w/neutropenia, thrombocytopenia, and TTP.

Front 252

252. Clopidogrel

Back 252

Used in combo w/aspirin for improved platelet inhibition during and after surgery (especially interventional radiology)

Prodrug that must undergo oxidation by hepatic p450 3a4 enzyme

Approved for secondary prevention in patients w/recent MI, stroke, or peripheral vascular disease.

Requires a loading does to achieve max antiplatelet effect rapidly

Adverse effect is wear and tear of GI system.

Front 253

253. GPIIb/IIIa antagonists

Back 253

Prevents fibrinogen binding to GPIIb/IIIa receptor and serves as powerful inhibitor of platelet aggregation.

Front 254

254. Eptifibatide

Back 254

Highly efficacious inhibitor of platelet aggregation

Antagonizes platelets GPIIb/IIIa

Used to reduce ischemic events in patients undergoing coronary surgery and to prevent unstable angina and non ST elevation MI

Front 255

255. Abciximab

Back 255

Chimeric mouse human monoclonal antibody directed against human GPIIb/IIIa receptor.

Binding is essentially irreversible w/dissociation half time of 18-24 hrs.

Reduces both long term/short term ischemic events in patients undergoing high risk percutaneous surgery (i.e. coronary artery)

Front 256

256. Tirofiban

Back 256

Non-peptide tyrosine analogue that reversibly antagonizes fibrinogen binding to platelet GPIIb/IIIa

Approved for use in patients w/acute coronary syndromes.

Front 257

257. Anticoagulant classes

Back 257

1. Warfarin
2. Unfractionated and LMW heparins
3. Selective Factor 10a inhibitors
4. Direct thrombin inhibitors

Bleeding is an adverse effect common to all anticoagulants

Target various factors in the coagulation cascade thereby interrupting the cascade and preventing the formation of stable fibrin meshwork

Front 258

258. Mechanism of action of Vitamin K

Back 258

Vitamin K is required for the normal hepatic synthesis of four coagulation factors (2, 7, 9, and 10), protein C, and protein S.

These proteins gain biological activity by post-translational carboxylation of their 9 to 12 amino-terminal glutamic acid residues.

Thus, vitamin K-dependent carboxylation is crucial for the enzymatic activity of the four coagulation factors and protein C, and for the cofactor function of protein S.

Front 259

259. What does the carboxylation reaction require?

What happens during this reaction?

Back 259

1. A precursor form of the target protein with its 9 to 12 amino-terminal glutamic acid residues
2. Carbon dioxide
3. Molecular oxygen
4. Reduced vitamin K

During this reaction, vitamin K is oxidized to the inactive 2,3-epoxide.

An enzyme, epoxide reductase, is then required to convert the inactive 2,3-epoxide into the active, reduced form of vitamin K.

Front 260

260. Warfarin

Back 260

Warfarin acts on the carboxylation pathway, not by inhibiting the carboxylase directly, but by blocking the epoxide reductase that mediates the regeneration of reduced vitamin K.

Because depletion of vitamin K in the liver prevents the carboxylation reaction required for synthesis of biologically active coagulation factors the onset of action of the oral anticoagulants parallels the half-life of these coagulation factors in the circulation.

Thus, the pharmacological effect of a single does of warfarin is not manifested for approx 18-24 hours.

Front 261

261. What is the molecular target of oral anticoagulant action?

Back 261

Epoxide reductase

Mutations in some patient's epoxide reductase gene can lead to genetic resistance to warfarin; these patients require 10-20 times the usual does of warfarin to achieve the desired anticoagulant effect.

Front 262

262. What are the clinical uses of warfarin?

Back 262

Warfarin is often administered to complete a course of anticoagulation that has been initiated with heparin and to prevent thrombosis in predisposed patients.

Orally administered warfarin is nearly 100% bioavailable, and its levels in the blood peak at .5 to 4 hours after administration.

In the plasma, 99% of racemic warfarin is bound to plasma protein (albumin)

Half life of warfarin is approx 36 hours and is hydroxylated by cytochrome p450 enzyme.

Front 263

263. Drug-drug interactions with warfarin

Back 263

B/c warfarin is highly albumin-bound in the plasma, coadministration o f warfarin w/other albumin-bound drugs can increase the free plasma concentrations of both drugs.

In addition, b/c warfarin is metabolized by p450 enzymes in the liver, coadministration of warfarin w/drugs that induce and/or compete for p450 metabolism can affect the plasma concentrations of both drugs.

Front 264

264. Adverse effects of warfarin

Back 264

Bleeding is the most serious and predictable toxicity.

Patients w/severe hemorrhage should receive fresh frozen plasma, which contains biologically functional clotting factors 2, 7, 9, and 10.

Warfarin should never be administered to pregnant women b/c it can cross the placenta and case a hemorrhagic disorder in the fetus.

In addition, newborns exposed to warfarin in utero may have serious congenital defects characterized by abnormal bone formation.

Front 265

265. If warfarin is an anticoagulant, how can it cause thrombosis?

Back 265

In addition to inhibiting the synthesis of biologically active coagulation factors 2, 7, 9, and 10, warfarin also prevents the synthesis of biologically active proteins C and S, which are natural anticoagulants.

In patients who are genetically deficient in protein C or S, an imbalance between the warfarin's effects on coagulation factors and its effects on proteins C and S may lead to microvascular thrombosis and skin necrosis.

Front 266

267. Monitoring of warfarin therapy

Back 266

Most easily performed using the prothrombin time (PT), which is a simple test of the extrinsic and common pathways of cagulation.

Warfarin prolongs the PT mainly b/c it decreases the amount of biologically functional factor 7 in the plasma (remember Factor 7 is the vitamin K dependent coagulation factor w/the shortest half-life.)

Front 267

268. Heparin

Back 267

A sulfated mucopolysaccharide stored int he secretory granules of mast cells. It is a highly sulfated polymer of alternating uronic acid and D-glucosamine.

Heparin molecules are highly negatively charged; indeed, endogenous heparin is the strongest organic acid in the human body.

Molecular weights range from 1 to 30 kDa.

Unfractionated heparin, which is often prepared from bovine lung and porcine intestinal mucosa, ranges in molecular weight from 5 to 30 kDA.

LMW heparins are prepared from standard heparin by gel filtration chromatography; their molecular weight range from 1 to 5 kDA

Front 268

269. What is heparin's mechanism of action?

Back 268

Depends on the presence of a specific plasma protease inhibitor, antithrombin III.

ATIII is essentially a suicide trap for serine proteases, and prevents the proteases from further participation in the coagulation cascade.

In the absence of heparin the binding reaction between the proteases and ATIII proceeds slowly.

Heparin, acting as a cofactor, accelerates the reaction by 1,000x.

Front 269

270. Two important physiologic functions of heparin

Back 269

1. It serves as a catalytic surface to which both ATIII and the serine proteases bind

2. It induces a conformational change in ATIII that makes the reactive site of this molecule more accessible to the attacking protease.

Front 270

271. Heparin scaffolding

Back 270

To catalyze most efficiently the inactivation of thrombin by ATIII, a single molecule of heparin must bind simultaneously to both thrombin and antithrombin.

This scaffolding function of heparin is required in addition to the heparin-induced conformation change in ATIII that renders the antithrombin susceptible to conjugation w/thrombin.

In contrast, to catalyze the inactivation of factor 10a by ATIII, the heparin molecule must bind only to the antithrombin, b/c the conformational change in ATIII induced by heparin binding is sufficient by itself to render the antithrombin susceptible to conjugation with factor 10a

Front 271

272. LMW heparins

Back 271

Have an avg of only 3-4 kDa, and contain fewer than 18 monosaccharide units.

They efficiently catalyze the inactivation of factor 10a by ATIII but less efficiently catalyze the inactivation of thrombin by ATIII.

Front 272

273. Unfractionated heparins

Back 272

Have an avg weight of 20 kDa and contains more than 18 monosaccharide units, is of sufficient length to bind simultaneously to thrombin and ATIII, and therefore efficiently catalyzes the inactivation of both thrombin and factor 10a by ATIII.

Front 273

274. Summary comparison of LMW to unfractionated heparin

Back 273

LMW heparin has a 3x higher ratio of anti-10a to anti-thrombin activity than does unfractionated heparin.

LMW heparin is therefore a more selective therapeutic agent than unfractionated heparin.

Both LMW hepain and unfractionated heparin use a pentasaccharide structure of high negative charge to bind ATIII and to induce the conformation change in antithrombin required for the conjugation reactions.

Front 274

275. Clinical uses of heparins

Back 274

Used for both prophylaxis and treatment of thromboembolic diseases. Both unfractionated and LMW heparins are used to prevent propagation of established thromboembolic disease such as DVT and pulmonary embolisms.

Heparins are highly negatively charged, and therefore, neither unfractionated nor LMW heparin can cross the epithelial cell layer of the GI tract; hence, heparin must e administered parenterally, usually via IV

Front 275

276. Clinical uses of unfractionated heparin

Back 275

Often used in combination with antiplatelet agents in the treatment of acute coronary syndromes

Monitoring of the unfractionated heparin therapy is important for maintaining the anticoagulant effect within the therapeutic range, because excessive heparin administration significantly increases the risk of bleeding and thrombocytopenia

Monitoring can be done using the activated partial thromboplastin time

Front 276

277. Differences between heparin induced thrombocytopenia (HIT) type 1 and 2?

Back 276

In type 1, the antibody coated platelets are targeted for removal from the circulation, and the platelet count decreases by 50-75% approx 5 days into the course of heparin therapy. It is transient and rapidly reversible upon heparin withdrawal.

In type 2, however, the heparin-induced antibodies not only target the platelets for destruction but also act as agonists to activate the platelets leading to platelet aggregation, endothelial injury, and potentially fatal thrombosis.

There is a higher incidence of HIT in patients receiving unfractionated heparin than in those receiving LMW heparin.

Front 277

278. LMW heparins

Back 277

1. Enoxaparin
2. Dalteparin
3. Tinzaparin

These agents are relatively slevetive for anti-10a compared to anti-2a (antithrombin) activity.

They have highertherpeutic index than unfractionated heparin, especially when used for prophylaxis.

For this reason it is generally not necessary to monitor blood activity levels of LMW heparins; instead use a specialized assay.

Because LMW heparins are excreted via the kidneys, care should be taken to avoid excessive anticoagulation in patients with renal insufficiency.

Front 278

279. Example of a selective Factor 10a inhibitor

Back 278

Fondaparinux

-Binds to ATIII via pentasaccharide which is sufficient to inactivate 10a.

Front 279

280. Fondaparinux

Back 279

Synthetic pentasaccharide molecule that contains the sequence of five essential carbs necessary for binding to ATIII and inducing the conformational change in antithrombin required for conjugation to factor 10a.

This agent is therefore a specific inhibitor of 10a, with negligible anti-2a (anti-thrombing) activity.

Approved for prevention and treatment of DVT and is available as a once daily subcutaneous injection.

It is excreted via the kidneys and should not be administered to patients with renal insufficiency.

Front 280

281. Direct thrombin inhibitors

Back 280

1. Lepirudin
2. Desirudin
3. Bivalirudin
4. Argatroban

These agents are specific inhibitors of thrombin, with negligible anti-factor 10a activity.

Front 281

282. Lepirudin

Back 281

A recombinant 65 AA derived from the medicinal leech protein hirudin.

It binds w/high affinity to two sites on the thrombin molecule, the enzymatic active site and a region of the thrombin protein that orients substrate proteins.

This binding prevents the thrombin mediated activation of fibrinogen and Factor 13.

It is a highly effect anticoagulant because it can inhibit bot free and fibrin-bound thrombin in devloping clots, and because lepirudin binding to thrombin is essentially irreversible.

Front 282

283. Clinical uses and adverse effects of lepirudin

Back 282

Approved for use in the treatment of heparin induced thrombocytopenia (HIT).

It has a short half life and is renally excreted.

Bleeding is the major adverse effect, and clotting times must be monitored closely.

A small percentage of patients may develop anti-hirudin antibodies, limiting the long-term effectiveness of this agent as an anticoagulant.

Front 283

284. Desirudin

Back 283

This is another recombinant formulation of hirudin, and has been approved for prophylaxis against DVT in patients undergoing hip replacement.

Front 284

285. Bivalirudin

Back 284

Synthetic 20 AA peptide that binds to both the active site and exosite of thrombin and thereby inhibits thrombin activity.

Approved for anticoagulation in patients undergoing coronary angiography and angioplasty, and may reduce rates of bleeding relative to heparin.

Front 285

286. Argatroban

Back 285

A small molecule inhibitor of thrombin that is approved for the treatment of patients with heparin induced thrombocytopenia (HIT).

Unlike other direct thrombin inhibitors, argatroban binds only to the active site of thrombin, and it also is excreted by biliary secretion.

Thus, it is safe to administer argatroban to patients with renal insufficiency.

Front 286

287. Recombinant activated protein C (r-APC)

Back 286

Endogenously activated protein C (APC) exerts an anticoagulant effect by proteolytically cleaving factors 5a and 8a. APC also reduces the amount of circulating plasminogen activator inhibitor 1, thereby enhancing fibrinolysis. Also, APC reduces inflammation by inhibiting the release of TNF-α by monocytes.

r-APC has been found to significantly reduce mortality in patients at high risk of death from septic shock, and the US FDA has approved r-APC for the treatment of patients with severe sepsis who demonstrate evidence of acute organ dysfunction shock, oliguria, acidosis, and hyoxemia.

It is not indicated for the treatment of patients with severe sepsis and a lower risk of death, however.

Also increases the risk of bleeding as do other anticoagulants.

Front 287

287. Thrombolytic agents

Back 287

1. Streptokinase
2. t-PA
3. Tenecteplase
4. Reteplase

These agents are used to lyse already-formed clots, and thereby to restore the patency of an obstructed vessel before distal tissue necrosis occurs.

They act by converting the inactive zymogen plasminogen to the active protease plasmin.

Front 288

288. Streptokinase

Back 288

A protein produced by β-hemolytic streptococci as a component of that organisms' tissue destroying machinery.

The pharmacologic action of streptokinase involves two steps: complexation and cleavage.

In complexation reaction, streptokinase forms a stable, noncovalent 1:1 complex with plasminogen which produces a conformational change in plasminogen that exposes this protein's proteolytically active site.

This complexed plasminogen can then proteolytically cleave other plasminogen molecules to form plasmin.

Front 289

289. Clinical uses of streptokinase

Back 289

Beneficial effects limited by two factors:

1. It is a foreign protein that is capable of eliciting antigenic responses in humans upon repeated administration.

2. The thrombolytic actions of streptokinase are relatively nonspecific and can result in systemic fibrinolysis.

Currently, it is approved for treatment of ST elevation MI and for treatment of life threatening pulmonary embolism.

Front 290

290. Clinical uses for t-PA

Back 290

Generically referred to as alteplase
Approved for use in those with ST elevation MI or life threatening pulmonary embolism.

Also approved for the treatment of acute ischemic stroke.

Its use is contraindicated in patients who have had a recent hemorrhagic stroke.

Front 291

291. Tenecteplase

Back 291

A genetically engineered variant of t-PA.

The molecular modifications in tenecteplase increases its fibrin specificity relative to t-PA and make tenecteplase more resistant to plasminogen activator inhibitor 1.

Trials have shows that tenectepalse is identical in efficacy to t-PA with similar and possibly decreased risk of bleeding.

Additionally, it has a longer half life than t-PA, which allows it to be administered as a single weight based bolus, thus simplifying administration.

Front 292

292. Reteplase

Back 292

Similar to tenecteplase, reteplase is a genetically engineered variant of t-PA with longer half life and increase specificity for fibrin. Its efficacy and adverse effect profile are similars to those of streptokinase and t-PA.

B/c of its longer half life, retepalse can be administered as a "double bolus".

Front 293

293. Inhibitors of anticoagulation and fibrinolysis

Back 293

1. Protamine
2. Aprotinin
3. Aminocaproic acid
4. Tranexamic acid

Front 294

294. Protamine

Back 294

A LMW polycationic protein; is a chemical antagonist of heparin.

This agent rapidly forms a stable complex with the negatively changed heparin molecule thru multiple electrostatic interactions.

Administered IV to reverse the effects of heparin in situations of life threatening hemorrhage or great heparin excess.

Most active against the large heparin molecules in unfractionated heparin and it can partially reverse the anticoagulant effects of LMW heparins, but it is inactive against fondaparinux.

Front 295

295. Aprotinin

Back 295

A naturally occurring polypeptide, is an inhibitor of the serine proteases plasmin, t-PA, and thrombin.

By inhibiting fibrinolysis, aprotinin promotes clot stabilization.

Inhibition of thrmobin may also promote platelet activity by preventing platelet hyperstimulation.

At higher does, however, it may also inhibit kallikrein and hereby inhibit the coagulation cascade.

Used to decrease perpioperative bleefing and erythrocyte transfusion requirement in patients treated with aproptinin during cardiac surgery.

However, it may also increase the risk of postoperative acute renal failure

Front 296

296. Aminocaproic acid and tranexamic acid

Back 296

Both are analogies of lysine that bind to and inhibit plasminogen and palsmin.

Like aprotinin, these agents are used to reduce perioperative bleeding during coronary artery bypass grafting.

Unlike aprotinin, these agents may not increase the risk of postoperative acute renal failure.

Front 297

297. Anasarca

Back 297

Severe systemic edema

Front 298

298. Noninflammatory causes of edema

Back 298

1. Increased hydrostatic pressure forces fluid out of the vessels due to increased venous return from CHF, liver cirrhosis, venous obstruction, etc...

2. Reduced plasma osmotic pressure (hypoproteinemia)

3. Lymphatic obstruction

4. Sodium retention

Front 299

299. Subcutaneous edema

Back 299

May be diffuse or occur where hydrostatic pressures are greatest

Dependent edema is typical of CHF

Edema resulting from hypoproteinemia is generally more severe and diffuse; it is most evident in the loss connective tissue (e.g. eyelids, causing periorbital edema)

Front 300

300. Pulmonary edema

Back 300

Typical in left ventricular failure but is also seen with renal failure, adult respiratory distress syndrome, infections, and hypersensitivity reactions.

The lungs are 2-3x their normal weight; sectioning reveals a frothy, blood tinged mixture of air, edema fluid, and erythrocytes

Front 301

301. Brain edema

Back 301

May be localized to sites of injury or may be generalized (e.g. encephalitis, hypertensive crises, or obstruction to venous outflow)

When generalized, the brain is grossly swollen w/narrowed sulci and distended gyri flattened against the skull.

Front 302

302. Hyperemia vs. congestion

Back 302

Both terms mean increased volume of blood in a particular site

Hyperemia is an active process due to augmented blood inflow from arteriolar dilation. Tissues are redder owing to engorgement with oxygenated blood.

Congestion is a passive process caused by impaired outflow from a tissue. Isolated venous obstruction may cause local congestion; systemic venous obstruction occurs in CHF. Tissues are blue-red.

Front 303

303. Acute congestion vs. chronic congestion

Back 303

Vessels are distended and organs are grossly hyperemic; capillary bed congestion is also commonly associated with interstitial edema.

In chronic congestion, capillary rupture may cause focal hemorrhage; subsequent erthrocyte breakdown result in hemosiderin laden macrophages. Grossly, tissues appear brown, contracted, and fibrotic. Lungs and liver are commonly affected.

Front 304

304. When are the lungs involved?

When is the liver involved?

Back 304

Lungs are involved in left ventricular failure of any cause.

Liver is involved in right sided heart failure or rarely with hepatic vein or IVC obstruction.

Front 305

305. Hemorrhage

Back 305

Refers to blood extravasation following vessel rupture.

Hemorrhage may be external or enclosed within a tissue; the latter is called a hematoma.

Front 306

306. How are hemorrhages categorized?

Back 306

Petechia; minute 1-2 mm

Purpura; larger (=>3mm)

Ecchymoses; larger (> 1-2cm)

Large accumulations of blood in the body cavities are called hemothorax, hemopericardium, hemoperitoneum, or hemarthrosis, depending on the location.

Front 307

307. Color changes in hemorrhages

Back 307

1. Erythrocytes in hemorrhages are degraded by macrophages.
2. The hemoglobin (red-blue color) is converted to bilirubin and biliverdin (blue-green color)
3. These are then eventually converted to hemomsiderin (golden brown), accounting for the characteristic color changes in a bruise.

Patients with extensive hemorrhages occasionally develop jaundice from massive erythrocyte breakdown and systemic bilirubin release.

Front 308

308. Primary genetic causes of hypercoagulable states

Back 308

1. Factor 5 Leiden
2. Mutation in prothrombin gene
3. Mutation in methyltetrahydrofolate gene
4. ATIII deficiency
5. Protein C deficiency
6. Protein S deficiency

Front 309

309. Antiphospholipid antibody syndrome

Back 309

Occurs in patients with antibodies against anionic phospholipids that can putatively activate platelets or interfere with protein C activity.

Patients may have well defined autoimmune disease or may exhibit only a hypercoagulable state.

Front 310

310. Cardiac and arterial thrombi

Back 310

Are gray-red and have gross microscopic laminations (lines of Zahn) produced by pale layers of platelets and fibrin alternating with darer erythrocyte rich layers.

Major sites include the left ventricle overlying an infarct ruptured atherosclerotic plaques, and aneurysmal sacs.

Front 311

311. Venous thrombosis

Back 311

AKA phlebothrombosis

Often creates a long red-blue cast of the vein lumen b/c it occurs in a relatively static environment.

The thrombus contains more enmeshed erythrocytes among sparse fibrin strands (red or stasis thrombi).

Fibrin and vessel wall attachment distinguish stasis thrombi from postmortem clots.

Most commonly affects the veins of the lower extremities (>90% of cases).

Front 312

312. Where else do thrombi form?

Back 312

On heart valves

In infective endocarditis, organisms form large infected thrombotic masses causing underlying valve damage and systemic infection

Also in nonbacterial thrombotic endocarditis, sterile vegetations also develop on noninfected valves in hypercoagulable states, particularly in those with malignancies.

Front 313

313. What is the fate of the thrombi?

Four different fates...

Back 313

1. Propagation, causing complete vessel obstruction

2. Embolization to other sites in the vasculature is especially common with lower extremity venous thrombi embolizing to the lung.

3. Dissolution by fibrinolytic activity

4. Organization and recanalization, reestablishing flow by ingrowth of endothelial cells, smooth muscle cells, and fibroblasts to create vascular channels, or by incorporating the thrombus as a subendothelial swelling of the vessel wall.

Front 314

314. Superficial thrombi

Back 314

Usually occur in varicose saphenous veins, causing local congestion and pain but rarely embolizing.

Local edema and impaired venous drainage predispose to skin infections and varicose ulcers

Front 315

315. Deep thrombi

Back 315

Are in larger leg veins above the knee and more readily embolize.

Although they may cause pain and edema, venous obstruction is usually offset by collateral flow. Thus, deep vein thromboses are entirely asymptomatic in approx 50% of patients and are recognized only after embolization.

Front 316

316. Clinical settings in which DVT occurs

Back 316

1. Advanced age, bed rest, or immobilization
2. CHF
3. Trauma, surgery, and burns result in reduced physical activity, injury to vessels, release of procoagulant substances from tissues, and reduced tPA
4. The puerperal and postpartum states are associated w/amniotic fluid embolization and hypercoagulability
5. Tumor associate procoagulant release, causing the thrombosis seen with malignancies

Front 317

317. Arterial thrombosis

Back 317

Brain, kidneys, and spleen are prime targets.

MI w/dykinesis and endocardial damage may result in mural thrombi.

Rhematic valvular disease can cause mitral valve stenosis, followed by left atrial dilation and thrombus formation within the atrium or auricular appendiages

Major cause is from atherosclerosis!

Front 318

318. Disseminated intravascular coagulation

Back 318

Refers to widespread fibrin microthrombi in the microcirculation.

This is caused by disorders ranging from obstretric complications to advanced malignancy.

DIC is not a primary disease but rather a complicationof any diffuse thrombin activation.

The microthrombi can cause diffuse circulatry insufficiency, particularly in the brian, lungs, heart, and kidneys; there is also concurrent consumption of platelets and coagulation factors with fibrinolytic pathway activation, leading to uncontrollable bleeding.

Front 319

319. Pulmonary thromboembolism

Back 319

Greater than 95% of pulmonary emboli originate from deep leg vein thrombi; depending on the size, a pulmonary emoblus may occlude the main pulmonary artery, impact across the bifurcation or pass into smaller arterioles.

One PE puts a patient at risk for more.

Sudden death, right sided heart failure (cor pulmonale) or cardiovascular collapse occurs when 60% or more of the pulmonary circulation is obstructed with emboli.

Multiple PE over time may cause pulmonary hypertension

Front 320

320. Systemic thromboembolism

Back 320

Refers to emboli in the arterial circulation.

Approx 80% arise from intracardiac mural thrombi

Major sites are the lower extremities, brain, viscera, and upper extremities.

Front 321

321. Fat embolism

Back 321

The second most common form of embolism.

It results from release of microscopic fat globules after fractures of long bones or rarely, after burns or soft tissue trauma.

Occurs in 90% of severe skeletal injuries; fewer than 10% have any clinical findings

Front 322

322. Fat embolism syndrome

Back 322

Fatal in approx 10% of cases, is heralded by sudden pulmonary insuffiency 1 to 3 days after injury

20 o 50% of patients have a diffuse petechial rash and may have neurological symptoms that progress to delirium or coma.
Thombocytopenia and anemia can also occur.

Front 323

323. Pathogenesis involved in fat embolism syndrome

Back 323

Involves mechanical obstruction by microemboli of neutral fat, followed by local platelet and erthrocyte aggregation.

Subsequent fatty acid release causes toxic injury to endothelium; platelet activation and granulocyte recruitment contribute free radicals, proteases, and eicosanoids.

Front 324

324. Dx of fat embolism syndrome

Back 324

Depends on identifying microvascular fat globules. Because routine histologic solvents dissolve lipids out of tissues, documentation requires special fat stains.

Edema and hemorrhage may also be seen microscopically.

Front 325

325. Air embolism

Back 325

Refers to gas bubbles withing the circulation obstructing vascular flow and causing ischemia.

Air may enter during obstetric procedures or following chest wall injury; generally, more than 100 cc are required to have a clinical effect.

Front 326

326. Decompression sickness

Back 326

A special form of air embolism caused by sudden changes in atmospheric pressure.

Air breathed at high pressure causes increasing amounts of gas to be dissolved in blood and tissues.

Subsequent rapid depressurization allows the dissolved gases to expand and bubble out of the solution to form gas emboli.

Treatment consists of re-pressurizing to force gas bubbles back into solution, followed by subsequent slow decrompression.

Front 327

327. Caisson disease

Back 327

Persistent gas emboli in poorly vascularized portions of the skeleton and leads to ischemic necrosis.

Front 328

328. Amniotic fluid embolism

Back 328

Serious but uncommon complication of labor and postpartum period caused by amniotic fluid infusion into the maternal circulation.

Classic findings include fetal squamous cells, mucin, lanugo hair, and vernix caseosa fat in the maternal pulmonary microcirculation.

Characterized by sudden server dyspnea, cyanosis, and hypotensive shock, followed by seizures and coma.

Pulmonary edema, diffuse alveolar damage, and DIC ensure from release of toxic and thrombogenic substances in the amniotic fluid.

Front 329

329. Where do red infarcts occur?

Back 329

1. Venous occlusions
2. Loose tissues (lungs)
3. Tissues w/dual circulations (i.e. lung and small intestine)
4. Tissues previously congested because of sluggish venous outflow
5. Sites of previous occlusion and necrosis when flow is reestablished.

Front 330

330. Where do white infarcts occur?

Back 330

In solid organs (such as heart,spleen, and kidney) with end-arterial circulation (i.e. few collaterals)

Front 331

331. Common characteristics of infarcts

Back 331

All infarcts tend to be wedge shaped; the occluded vessel marks the apex, and the organ periphery forms the base

Dominant histologic signs is ischemic coagulative necrosis, however, the brain does not exhibit this; instead, it results in liquefactive necrosis.

Septic infarctions occur when infected heart valve vegetations embolize or when microbes seed an area of necrosis; the infarct then becomes an abscess.

Front 332

332. Factors that influence development of an infarct

Back 332

1. Anatomic pattern of vascular supply
-dual circulations or anastomosing circulations protect against infarction.
2. Rate of development of occlusion
3. Vulnerability to hypoxia
4. Oxygen content of blood.

Front 333

333. Shock

Back 333

Shock is systemic hypoperfusion resulting from reduction in ether cardiac output or the effective circulating blood volume

The result is hypotension, followed by impaired tissue perfusion and cellular hypoxia.

Front 334

334. Basic mechanism underlying cardiogenic and hypovolemic shock

Back 334

Low cardiac output

Front 335

335. Septic shock

Back 335

Caused by systemic microbial infection and has a more complicated pathogenesis

Results form spread of an initally localized infection into the bloodsream

Most cases are caused by gram-negative bacilli expressing endotoxin (endotoxic shock)

Front 336

336. Bacterial lipopolysaccharides (LPS)

Back 336

Released when cell walls are degraded

Consists of a toxic fatty acid core and a complex polysaccharide

All the effects of septic shock are reproduced by LPS alone.

LPS binds to CD14 molecules on leukocytes, endothelial cells and other cells types

The LPS then interacts w/membrane toll-like receptor 4 (TLR-4) that transduces an intracellular signal

Front 337

337. TLR-4

Back 337

TLR-4 engagement profoundly activates cytokine and chemokine production; depending on LPS dosage and the numbers of macrophages activated there are different outcomes.

Front 338

338. Low doses of LPS

Back 338

Mainly activates complement and monocyte/macrophages, leading to enhanced bacterial eradication.

Net effect is enhanced local inflammatory response and improved clearance of infections

Front 339

339. Moderate doses of LPS

Back 339

Cytokine induced secondary effectors (e.g. NO) become significant. Also, systemic effects of TNF and IL1 are seen (e.g. fever)

Also down regulates EC anticoagulation mechanisms (i.e. reduced thrombomodulin), tipping the coagulation cascade toward thrombosis

Front 340

340. High doses of LPS

Back 340

Septic shock supervenes with high-level cytokines and secondary mediators resulting in:

1. Systemic vasodilation
2. Diminished myocardial contractility
3. Widespread endothelial injury and activation
4. Activation of the coagulation system, culminating in DIC

The resulting hypoperfusion causes multiorgan failure; unless the underlying infection (and LPS overload) is brought under control, the patient usually dies

Front 341

341. Signs of organ shock (brain, heat, kidneys, lungs)

Back 341

Brain: shows hypoxic encephalopathy

Heart: shows coagulation necrosis and contraction band necrosis

Kidneys: develop extensive tubular ischemic injury, causing oliguria anuria, and electrolyte disturbances

Lungs: seldom affected in pure hypovolemic shock; however, diffuse alveolar damage may occur in septic or traumatic shock

Front 342

342. What happens if the patient survives the initial complications of shock?

Back 342

Patients surviving the initial complications enter a second phase dominated by renal insufficiency and marked by a progressive fall in urine output, as well as sever fluid and electrolyte imbalances