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209 Cards in this Set

  • Front
  • Back
1. What does hemostasis mean?
Prevention of blood loss
2. When a vessel is severed or ruptured, what four mechanisms are needed to achieve hemostasis?
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
3. What causes vascular contraction after rupture to a blood vessel?
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
4. Platelets

How are they formed?

What is their concentration in the blood?
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
5. What are the characteristics of platelets?

How are they related to whole cells?
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
6. Cell membrane of platelets
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
7. What happens when platelets come in contact with a damaged vascular surface?
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
8. How are trauma and clotting time related?
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
9. When a blot clot has formed, what two options does it have?
1. It can become invaded by fibroblasts which subsequently form connective tissue all thru the clot

2. It can dissolve
10. Basic theory of blood coagulation
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.
11. General mechanism of blood coagulation - three steps
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.
12. Prothrombin
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.
13. Conversion of prothrombin to thrombin
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.
14. Fibrinogen
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.
15. Action of thrombin on fibrinogen
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.
16. Fibrin monomer bonding
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.
17. Clot retraction
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.
18. Vicious circle of clot formation
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.
19. How is prothrombin activator formed?
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.
20. Extrinsic pathway
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.
21. Extrinsic pathway in a nutshell
Tissue trauma

Tissue factor

7 → 7a; via tissue factor

10 → 10a; via 7a and calcium ions

Common pathway
22. Intrinsic pathway
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
23. Intrinsic pathway in a nutshell
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
24. Common cascade
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.
25. Role of calcium ions in the intrinsic and extrinsic pathways
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.
26. Important difference between the extrinsic and intrinsic pathways
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.
27. What are the most important factors for preventing clotting in the normal vascular system?
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.
28. Endothelial wall damage - what is the consequence?
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.
29. Antithrombin II
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.
30. Heparin
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.
31. Mast cells and basophils
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.
32. Plasminogen
AKA profibrinolysin

When activated, becomes a substance called plasmin.
33. Plasmin
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, it can cause lysis of a clot by destroying many of the clotting factors.
34. Lysis of clots
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.
35. Three important types of bleeding tendencies
1. Vitamin K deficiency

2. Hemophilia

3. Thrombocytopenia
36. What does vitamin K deficiency lead to?
Decreased levels of:
1. Prothrombin
2. Factor 7
3. Factor 9
4. Factor 10
37. Synthesis of vitamin K
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.
38. What is the most prevalent cause of vitamin K deficiency?
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.
39. Hemophilia
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.
40. Factor 8
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.
41. Therapy for prolonged bleeding in patients with classic hemophilia
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.
42. Thrombocytopenia
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"
43. Suspicion of thrombocytopenia without making specific platelet counts
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.
44. Most common form of thrombocytopenia
Idiopathic thrombocytopenia

In most of these people, specific antibodies have formed and react against the platelets themselves to destroy them.
45. Therapy for bleeding in patients with thrombocytopenia
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.
46. Difference between thrombi and emboli
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.
47. Cause of thromboembolic conditions
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
48. Use of t-PA in treating intravascular clots
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)
49. Disseminated intravascular coagulation (DIC)
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
50. Heparin as an IV anticoagulant
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.
51. Coumarins as anticoagulants
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.
52. How can we prevent blood from clotting in test tubes?
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.
53. How else can we prevent blood clotting outside of the body?
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.
54. Methods used to determine blood clotting times
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.
55. Prothrombin time
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.
56. Other methods used to determine blood clotting times via clotting factors
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.
57. What is polycythemia?
Polycythemia, or erythrocytosis, denotes an abnormally high concentration of RBCs, usually w/a corresponding increase in Hb level.

The increase in red cells can be relative, when there is hemoconcentration due to decreased plasma volume, or absolute when there is an increase in total red cell mass.
58. What is relative polycythemia?
Relative polycytemia results from any cause of dehydration, such as deprivation of water, prolonged vomiting, diarrhea, or excessive use of diuretics.
59. What is Gaisbock syndrome?
Relative polycythemia is also associated with an obscure condition of unknown etiology called stress polycythemia, or Gaisbock syndrome. Affected individuals are usually hypertensive, obese, and anxious.
60. What is absolute polycythemia?
Absolute polycythemia is primary when it results from an intrinsic abnormality of the myeloid stem cells and secondary when the red cell progenitors are responding to increased levels of erythropoietin.

Primary polycythemia (polycythemia vera) is one of several neoplasms originating from myeloid stem cells.
61. What is congenital polycythemia?
Another much less common form of primary polycythemia results from mutations in the erythropoietin receptor that cause hyperresponsiveness to erythropoietin. Affected individuals have congenital polycythemia.
62. What can cause secondary polycythemia?
Secondary polycythemias can be caused by an increase in erythropoietin secretion that is physiologically appropriate (e.g., chronic hypoxia) or inappropritate (pathologic).
63. Excessive bleeding can result form what 4 things...?
1. Increased fragility of vessels
2. Platelet deficiency or dysfunction
3. Derangement of coagulation
4. Combination of these
64. What are bleeding time tests?
This measures the time taken for a standardized skin puncture to stop bleeding and provides and in vivo assessment of platelet response to limited vascualr injury.

The reference range depends on the method and varies from 2-9 minutes. Prolongation generally indicates a defect in platelet numbers or function.
65. How are platelet counts evaluated?
Platelet counts are obtained on anticoagulated blood using an electronic particle counter. The reference range is from 150-300 x 10^3 /uL.

Counts well outside this range need to be confirmed by a visual inspection of a peripheral blood smear, as clumping of platelets can cause spurious thrombocytopenia during automated counting, and high counts may be indicative of a myeloproliferative disorder.
66. What is PT?
Prothrombin time assay tests the extrinsic and common coagulation pathways. The clotting of plasma after addition of an exogenous source of tissue thromboplastin and calcium ions is measured in seconds.

*A prolonged PT can result from deficiency or dysfunction of factor 5, 7, 10, prothrombin, or fibrinogen.
67. What is PTT?
Partial thromboplastin time assay tests the intrinsic and common clotting pathways. The clotting of plasma after addition of kaolin, cephalin, and calicum ions is measured in seconds. Kaolin serves to activate the contact-dependent factor 12, and cephalin substitutes for platelet phospholipids.

Prolongation of the PTT can be due to deficiency or dysfunction of factor 5, 8, 9, 10, 11, or 12, prothrombin, or fibrinogen.
68. What are the infectious that can induce petechial and purpuric hemorrhages?
Many infections do this, but especially implicated are meningococcemia, other forms of septicemia, infective endocarditis, and several of the rickettsioses.

The involved mechanism is presumably microbial damage to the microvasculature (vasculitis) or DIC.
69. What 3 things are associated with microvascular bleeding resulting from impaired formation of collagens needed for support of vessel walls?
1. Scurvy
2. Ehlers-Danlos syndrome
3. Cushing syndrome
70. What is Henoch-Schonlein purpura?
Systemic hypersensitivity reaction of unknown cause characterized by purpuric rash, abdominal pain, polyarthralgia, and acute glomerulonephritis

Associated with vascular and glomerular mesangial deposition of immune complexes.
71. What is hereditary hemorrhagic telangiectasia?
Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by dilated, tortuous blood vessels with thin walls that bleed readily.

Bleeding can occur anywhere in the body but is most common under the mucous membranes of the nose (epistaxis), tongue, mouth, and eyes and throughout the GI tract.
72. What about systemic amyloidosis and bleeding disorders?
Amyloid infiltration of blood vessels can by due to systemic amyloidosis., which is associated with perivascular deposition fo amyloid and consequent weakening of blood vessel wall.

This is most commonly observed in plasma cell dyscrasias and is manifested as mucocutaneous petechiae.
73. What is thrombocytopenia?
A platelet count below 100,000/uL is generally considered to constitute thrombocytopenia. However, spontaneous bleeding does not become evident until the count falls below 20,000/uL. Bleeding resulting from thrombocytopenia alone is associated with a prolonged bleeding time a normal PT and PTT.

Spontaneous bleeding associated with thrombocytpenia most often involves small vessels. The common sites of such hemorrhage are the skin and mucous membranes of the GI and GU tracts.
74. What are the 4 main categories of thrombocytpenia?
1. Decreased production of platelets
2. Decreased platelet survival
3. Sequestration
4. Dilutional
75. Decreased production of platelets can be due to...?
This can accompany generalized diseases of bone marrow such as aplastic anemia and leukemias or result from diseases that affect the megakaryocytes somewhat selectively. In vitamin B12 or folic acid deficiency, there is poor development and accelerated destruction of megakaryocytes w/in the bone marrow b/c DNA synthesis is impaired.
76. Decreased platelet survival can be due to?
This can be due to immunologic or nonimmunologic causes. In the immune conditions, platelet destruction is caused by circulating antiplatelet antibodies or immune complexes. The antiplatelet antibodies can be directed against self antigen on the platelets or against platelet antigens that differ among individuals.
77. What are common antigenic targets of both autoantibodies and alloantibodies?
The platelet membrane glycoprotein complexes IIb-IIIa and Ib-IX

Autoimmune thrombocytopenias include ITP, certain drug induced thrombocytopenias, and HIV.

Alloimmune thrombocytopenias arise when an individual is exposed to platelets from another person as may occur after blood transfusion or during pregnancy.
78. What about sequestions?
Thrombocytopenia, usually moderate in severity, may develop in any pt with marked splenomegaly. When necessary hypersplenic thrombocytopenia can be ameliorated by splenectomy.
79. What about dilutional thrombocytopenias?
Massive transfusions can produce a dilutional thrombocytopenia.

Blood stored for longer than 24 hours contains virtually no viable platelets; thus, plasma volume and red cell mass are reconstituted by transfusion, but the number of circulating platelets is relatively reduced.
80. What are the two clinical subtypes of primary ITP?
Acute and chronic; both are autoimmune disorders in which platelet destruction results from the formation of antiplatelet autoantibodies.
81. Immunologically mediated destruction of platelets occurs in what settings?
SLE, AIDS, after viral infections, and as a complication of drug therapy.

These secondary forms of immune thrombocytopenia can sometimes mimic the idiopathic autoimmune variety, and this Dx should be made only after exclusion of other known causes of thrombocytpenia.

***SLE is a very important cause***
82. What causes chronic ITP?
Chronic ITP is caused by the formation of autoantibodies against platelet membrane glycoproteins, most often IIb-IIIa, or Ib-IX in 80% of pts. In the majority of cases, the antiplatelet antibodies are of the IgG class.
83. How do these autoantibodies cause chronic ITP?
Opsonized platelets are rendered susceptible to phagocytosis by the cells of the mononuclear phagocyte system. Splenectomy is helpful, since the spleen is the major site of removal of sensitized platelets.

There is some evidence that megakaryocytes may be damaged by autoantibodies, leading to impairment of platelet production.
84. What are the principal morphological lesions of thrombocytopenic purpura?
They are found in the spleen and bone marrow but they are not diagnostic. The spleen is normal in size. There is congestion of the sinusoids and hyperactivity and enlargement of the splenic follicles, manifested by the formation of prominent germinal centers. In many instances, scattered megakaryocytes are found w/in the sinuses and sinusoidal walls. This may represent a very mild form of extramedullary hematopoiesis driven by elevated levels of thrombopoietin.
85. What is the importance of the bone marrow exam in thrombocytopenia?
Bone marrow reveals a modestrly increased number of megakaryocytes. Some of apparently immature, w/large, nonlobulated single nuclei.

The improtance of the bone marrow exam is to rule out thrombocytopenias resulting from bone marrow failure. *A decrease in the number of megakaryocytes argues against the Dx of ITP.
86. What are the clinical features of chronic ITP?
Chronic ITP occurs most commonly in adult women younger than 40. The female to male ratio is 3:1. This disorder is often insidious in onset and is characterized by bleeding into the skin and mucosal surfaces.

Cutaneous bleeding is seen in the form of pinpoint hemorrhages (petechiae), especially prominent in the dependent areas where the capillary pressure is higher. Petechiae can beceom confluent, giving rise to ecchymoses. Often, there is a history of easy bruising, nosebleeds, beleding from the gums, and hemorrhages into soft tissues w/minor trauma.

The disease may manifest first w/melena, hematuria, or excessive menstrual flow. *Subarachnoid hemorrhage and IC hemorrhage are serous consequences.
87. What supports the destruction of platelets being the cause of thrombocytopenia?
The findings of a low platelet count and normal or increased megakaryocytes in the bone marrow. The bleeding time is prolonged, but PT and PTT are normal. Therefore, a Dx of ITP should be made only after other causes of platelet deficiencies have been ruled out.
88. What is acute immune thrombocytopenic purpura?
Like chronic ITP, this condition is caused by antiplatelet autoantibodies, but its clinical features are course are distinct.

Acute ITP is a disease of childhood. The onset of thrombocytopenia is abrupt and is preceded in many cases by a viral illness. Unlike the adult chronic form, the childhood disease is self-limited. Steroid therapy is indicated only if thrombocytopenia is severe.
89. What is drug induced thrombocytopenia?
The drugs most commonly involved are quinine, quinidine, sulfonamide antibiotics, and heparin. Heparin induced thrombocytopenia is important b/c this anticoagulant is sued widely.

*Most develop so-called type I thrombocytopenia, which occurs rapidly after onset of therapy, is modest in severity and clinically insignificant, and may resolve despite continuation of heparin therapy. It most likely results from a direct platelet-aggregating effect of heparin.
90. What is type II thrombocytopenia?
More severe; usually occurs 5-14 days after commencement of therapy and can, paradoxically, lead to life-threatening venous and arterial thrombosis.

It is caused by an immune reaction directed against a complex of heparin and platelet factor 4. It appears that heparin binding modifies the conformation of platelet factor 4, making it susceptible to immune recognition. Binding of antibody to platelet factor 4 produces immune complexes that activate platelets, promoting thrombosis even in the setting of marked thrombocytopenia.
91. What is HIV-associated thrombocytopenia?
This is the most common hematologic manifestation of HIV infection. Both impaired platelet production and decreased destruction are responsible. CD4 has also been demonstrated on megakaryocytes; infected megakaryocytes are prone to apoptosis and are impaired in terms of platelet production.

HIV infection also causes hyperplasia and dysregulation of B cells, which predispose to the development of immune-mediated thrombocytopenia.

Also, antibodies directed against platelet membrane glycoprotein IIb-III complexes are detected in some pts, which sometimes cross-react with HIV-associated gp120, and act as opsonins.
92. What is the pentad of TTP?
1. Fever
2. Thrombocytopenia
3. Microangiopathic hemolytic anemia
4. Transient neurologic deficits
5. Renal failure
93. What is HUS?
HUS is also associated with microangiopathic hemolytic anemia and thrombocytopenia but is distinguished from TTP by the absence of neurologic symptoms, the prominence of acute renal failure, and frequent affliction of children.
94. What are the common fundamental features in TTP and HUS?
Widespread formation of hyaline thrombi, comprised primarily of platelet aggregates, in the microcirculation.

Consumption of platelets leads to thrombocytopenia, and the intravascular thrombi provide a likely mechanism for the microangiopathic hemolytic anemia and widespread organ dysfunction.

PT and PTT are usually normal.
95. What enzyme is often deficient in TTP?
ADAMTS 13. This enzyme is designated "vWF metalloprotease" and it normally degrades very high molecular weight multimers of vWF.

In the absence of this enzyme, high molecular weight multimers of vWF accumulate in plasma and sometimes promote platelet microaggregate formation throughout the microcirculation, leading to the symptoms of TTP.
96. How is a deficiency of ADAMTS 13 acquired?
May be inherited or acquired. In many pts an antibody that inhibits vWF metalloprotease is detected. Much less commonly the pts have inherited an inactivating mutation in the gene encoding this enzyme.

*IT is important to consider the possibility of TTP in any pt presenting with thrombocytopenia and microangiopathic hemolytic anemia, as any delay in Dx and Tx can be fatal. Plasma exchange can be life saving b/c it provides the missing enzyme.
97. What about pts with HUS?
In contrast to TTP, most pts with HUS have normal levels of vWF metalloprotease.

One important cause in children and the elderly is infectious gastroenteritis caused by E. coli 0157:H7. It binds to and damages endothelial cells in the glomerulus and elsewhere, thus initiating platelet activation and aggregation. Affected children prseent with bloody diarrhea, ,and a few days later HUS makes its appearance.

In addition, HUS can also be seen in adults following exposures that damage endothelial cells.
98. What are the three classifications of congenital disorders of platelet function?
1. Defects of adhesions (Benard-Soulier syndrome)

2. Defects of aggregation (Glanzmann's thrombasthenia)

3. Disorders of platelet secretion (storage pool disorders)
99. What is Benard-Soulier syndrome?
Bleeding resulting from defective adhesion of platelets to subendothelial matrix is best illustrated by the autosomal recessive disorder Benard-Soulier syndrome, which is caused by an inherited defcieincy of the platelet membrane glycoprotein complex Ib-IX.

This glycoprotein is a receptor for vWF and is essential for normal platelet adhesion to subendothelial matrix.
100. What is Glanzmann's thrombasthenia?
Bleeding due to defective platelet aggregation is exemplified by Glanzmann's thrombasthenia, which is also transmitted as an autosomal recessive trait.

Thrombasthenic platelets fail to aggregate in response to ADP, collagen, epinephrine, or thrombin owing to deficiency or dysfunction of glycoprotein IIb-IIIa, a protein complex that participates in the formation of "bridges" between platelets by binding fibrinogen and vWF.
101. What are the two clinically significant acquired defects of platelet function?
1. Ingestion of aspirin and other NSAIDs, which significantly prolong the bleeding time

2. Uremia
102. How does the bleeding in factor deficiencies differ from platelet deficiencies?
The bleeding in factor deficiencies differs from platelet deficiencies in that spontaneous petechiae or purpura are uncommon. Rather, the bleeding is manifested by large post-traumatic ecchymoses or hematomas, or prolonged bleeding after a laceration or any form of surgical procedure.

Bleeding into the GI and urinary tracts, and particularly into weight bearing joints, is common.
103. What about vitamin K deficiency?
Vitamin K deficiency results in impaired synthesis of factors 2, 7, 9, and 10 and protein C.

Since the liver makes virtually all the clotting factors, severe parenchymal liver disease can be associated w/a hemorrhagic diathesis.
104. What are the causes of hemophilia A and von Willebrand disease?
These are caused by qualitative or quantitative defects involving the factor 8-vWF complex.

The two components of factor 8-vWF complex, synthesized separately, come together and circulate in the plasma as a unit that serves to promote clotting as well as platelet-vessel wall interactions necessary to ensure hemostasis.
105. What is the role of factor 8?
Factor 8 procoagulant protein is an intrinsic pathway component required for activation fo factor 10.

***Deficiency of factor 8 gives rise to hemophilia A
106. What is the role of vWF?
Circulating factor 8 is noncovalently associated with very large vWF multimers.

vWF also interacts w/several other proteins involved in hemostasis, including collagen, heparin, and platelet membrane glycoproteins (Ib-IX and IIb-IIIa).

***Glycoprotein Ib-IX serves as the major receptor for vWF.

*The most important function of vWF in vivo is to promote the adhesion of platelets to subendothelial matrix. vWF multimers also serve as a carrier for factor 8 and are important for its stability. A deficiency of vWF causes von Willebrand disease.
107. What is the ristocetin agglutination test?
Test for vWF levels. It measures the ability of ristocetin to promote the interaction between vWF and platelet membrane glycoprotein Ib. Multivalent ristocetin-dependent binding of vWF creates interplatelet "bridges," leading to the formation of platelet clumps (agglutination).

Thus, the degree of ristocetin-dependent platelet agglutination caused by the addition of patient plasma provides a bioassay for vWF.
108. What is the major source of vWF?
vWF is produced by endothelial cells and megakaryocytes . *Endothelial cells are the major source of subendothelial and plasma vWF.
109. What is the major source of factor 8?
Factor 8 is made in several tissues; sinusoidal endothelial cells and Kupffer cells in the liver and glomerular and tubular epithelial cells in the kidney appear to be important sites of synthesis.
110. What is von Willebrand disease?
von Willebrand disease is believed to be one of the most common inherited disorders of bleeding in humans. It is characterized by spontaneous bleeding from mucous membranes, excessive bleeding from wounds, menorrhagia, and a prolonged bleeding time in the presence of a normal platelet count.

In most cases it is transmitted as an autosomal dominant disorder.
111. What is type I von Willebrand disease?
Both type I and III von Willebrand disease are associated w/a reduced quantity of circulating vWF.

Type I, an autosomal dominant disorder, accounts for approx 70% of all cases and is relatively mild. Reduced penetrance and variable expressivity characterize this type, and hence clinical manifestations are varied.

There is a prolongation of the PTT in type I von Willebrand disease.
112. What is type IIII von Willebrand disease?
Type II (an autosomal recessive disorder) is associated w/extremely low levels of functional vWF, and the clinical manifestations are correspondingly severe.

B/c a severe deficiency of vWF has a marked affect on the stability of factor 8, some of the bleeding characteristics resemble those seen in hemophilia. There is a prolongation of the PTT.

*Type III disease is associated with deletions or frameshift mutations.
113. What is type II von Willebrand disease?
Type II disease is characterized by qualitative defects in vWF; there are several subtypes, of which type 2A is the most common. It is inherited as an autosomal dominant disorder.

***B/c of missense mutations, the vWF formed is abnormal, leading to defective multimer assembly. Large and intermediate multimers, representing the most active forms of vWF, are missing from plasma.

Type II disease accounts for 25% of all cases and is associated with mild to moderate bleeding.
114. Pts with von Willebrand disease have what bleeding time characteristics?
Pts with von Willebrand disease have a prolonged bleeding time despite a normal platelet count.

The plasma level of active vWF, measured as the ristocetin cofactor activity, is reduced. B/c vWF stabilizes factor 8 by binding to it, a deficiency of vWF gives rise to a secondary decrease in factor 8 levels. This will prolong the PTT time.
115. What is hemophilia A?
Hemophilia A is the most common hereditary disease associated w/serious bleeding. It is caused by a reduction in the amt or activity of factor 8. This protein serves as a cofactor for factor 9 in the activation of factor 10 in the coagulation cascade.

Hemophilia A is inherited as an X-linked recessive trait, and thus occurs in males and in homozygous females. (Can occur in heterozygous females due to inactivation of the normal X chromosome in most of the cells).

Approx 20% of pts have no family history; their disease is presumably caused by new mutations.
116. What are the various stages of clinical symptoms in hemophilia A?
Depends on levels of factor 8 activity.

Those w/less than 1% of normal activity develop severe disease; levels betwen 2-5% of normal are associated w/moderate disease; and pts w/6-50% of activity develop mild disease.

The variable degrees of factor 8 deficiency are explained by heterogeneity in the causative mutations?
117. Most severe deficiencies in hemophilia A result from what type of mutation?
Most severe deficiencies result from an unusual inversion involving the X chromosome that completely abolishes the synthesis of factor 8.
118. What are the clinical features of hemophilia A?
In all symptomatic cases, there is a tendency toward easy bruising and massive hemorrhage after trauma or operative procedures. In addition, spontaneous hemorrhages freq occur in the regions of the body normally subject to trauma, particularly the joints, where they are known as hemarthroses.

Recurrernt bleeding into the joints leads to progressive deformities that can be crippling.

*Petechiae are characteristically absent.
119. Pts with hemophilia A have what bleeding time characteristics?
They have a normal bleeding time, platelet count, and PT, and a prolonged PTT.

***These tests point to an abnormality of the intrinsic coagulation pathway.***
120. Why do patients bleed when the extrinsic pathway is intact in hemophilia A?
It appears that the chief role of the extrinsic pathway in hemostasis is to produce a limited initial burst of thrombin activation upon tissue injury. This is reinforced and amplified by a feedback loop whereby thrombin activates factors 9 and 11 of the intrinsic pathway.

In addition, high levels of thrombin are required to activate thrombin activatable fibrinolysis inhibitor, a factor that augments fibrin deposition by inhibiting fibrinolysis.

Thus, both inadequate coagulation and inappropriate clot removal contribute to the bleeding diathesis in hemophilia.
121. What is the treatment of hemophilia A?
Involves infusion of recombinant factor 8.

Approx 15% of pts w/low or absent factor 8 develop antibodies that bind to an inhibit factor 8; inhibitors are most likely to develop in pts with severe factor 8 deficiency possibly b/c the protein is perceived as foreign b/c it was never seen before by the immune system.
122. What is hemophilia B (AKA Christmas disease or factor 9 deficiency)?
Severe factor 9 deficiency produces a disorder clinically indistinguishable from factor 8 deficiency.

Like hemophilia A, the B form is inherited as an X-linked recessive trait and shows variable clinical severity. In about 14% of these pts, factor 9 is present, but nonfunctional. Also, the PTT is prolonged and the PT is normal.

Recombinant factor 9 is used for treatment.
123. What is DIC?
DIC is an acute, subacute, or chronic thrombohemorrhagic disorder occurring as a secondary complication in a variety of diseases.

It is characterized by activation of the coagulation sequence that leads to the formation of microthrombi throughout the microcirculation of the body, often in an uneven distribution. Sometimes the coagulaopathy is localized to a specific organ or tissue.

***As a consequence of the thrombotic diathesis, there is consumption of platelets, fibrin, and coagulation factors and, secondarily, activation of fibrinolytic mechanisms. These greatly aggregate the hemorrhagic diathesis.
124. What is the pathogenesis of DIC?
DIC is not a primary disease. It is a coagulopathy that occurs in the course of a variety of clinical conditions, such as obstetric complications, infections, neoplasms, massive tissue injury and misc conditions.
125. Clotting can be initiated by what two ways?
1. Extrinsic, which is triggered by the release of tissue factor
2. Intrinsic, which involves the activation of factor 12 by surface contact with collagen or other negatively charged substances.

Both pathways, thru a series of intermediate steps, result int the generation of thrombin, which in turn converts fibrinogen to fibrin. Once activated at the site of injury, thrombin further augments local fibrin deposition thru feedback activation of the intrinsic pathway and inhibition of fibrinolysis.
126. So what causes DIC again?
Could result from pathologic activation of the extrinsic and/or intrinsic pathways of coagulation or impairment of the clotting inhibiting influences.
127. What 2 major mechanisms trigger DIC?
1. Release of tissue factor or thromboplastic substances into the circulation
-Can be from the placenta in obstetric complications and the granules of leukemic cells in acute promyelocytic leukemia. Also common in gram-negative sepsis due to release of IL-1 and TNF.

2. Widespread injury to the endothelial cells.
-due to TNF in spetic shock, SLE, heat stroke, etc...
128. DIC is most likely to follow what disorders?
Obstetric complications, malignant neoplasia, sepsis, and major trauma.
129. DIC is most likely to occur in what cancers?
Acute promeylocytic leukemia and carcinomas of the lung, pancreas, colon, and stomach are most frequently associated with DIC.

These tumors release a variety of thromboplastic substances, including tissue factors, proteolytic enzymes, mucin, and other undefined tumor products.
130. What are the 2 major consequences of DIC?
1. There is widespread deposition of fibrin w/in the microcirculation, which leads to ischemia of the more severely affected organs and to a hemolytic anemia resulting from fragmentation of red cells.

2. A hemorrhagic diathesis can dominate the clinical picture. This results from consumption of platelets and clotting factors as well as activation of plasminogen. Plasmin can not only cleave fibrin, but also digest factors 5 and 8, thereby reducing their concentration further.

*All these influences lead to the hemostatic failure seen in DIC.
131. Where are thrombi most likely to be found in DIC?
In decreasing order of freq:
1. Brain
2. Heart
3. Lungs
4. Kidneys
5. Adrenals
6. Spleen
7. Liver
132. What is the morphology of DIC in the lungs?
Numerous fibrin thrombi may be found in alveolar capillaries, sometimes associated w/pulmonary edema and fibrin exudation, creating "hyaline membranes" reminiscent of ARDS.
133. What is the morphology of DIC in the CNS?
Fibrin thrombi can cause microinfarcts, occasionally complicated by simultaneous hemorrhage. Such changes are the basis for the bizarre neurologic signs and symptoms sometimes observed in DIC.
134. What are two special endocrine conditions that are caused by a form of DIC?
1. Waterhouse-Friderichsen syndrome
2. Sheehan postpartum pituitary necrosis.
135. What are the clinical features of DIC?
The onset can be fulminant, as in endotoxic shock or amniotic fluid embolism, or insidious and chronic, as in cases of carcinomatosis or retention of a dead fetus.

Overall, about 50% of pts with DIC are obstetric pts having complications of pregnancy. In this setting, the disorder tends to be reversible with delivery of the fetus.
136. Lastly, how does acute DIC differ from chronic DIC?
In general, acute DIC, associated with obstetric complications or major trauma, for example, is dominated by a bleeding diathesis, whereas chronic DIC, such as occurs in CA pts, tends to present initially with thrombotic complications.
137. What are glucocorticoids?

How do they act?
Glucocorticoids have broad anti-inflammatory effects. They are steroid hormones that exert their physiologic actions by binding to the cytosolic glucocorticoid receptor. The glucocorticoid-glucocorticoid receptor complex translocates to the nucleus and bind to glucocorticoid response elements in the promoter region of specific genes, either up-regulating or down-regulating gene expression.
138. What are the important metabolic effects of glucocorticoids?
They down-regulate expression of inflammatory mediators, including key cytokines such as TNF-alpha, IL-1, and IL-4.
139. What are the drawbacks on long-term glucocorticoid use?
Diabetes, reduced resistance to infection, osteoporosis, cataracts, increased appetite leading to weight gain, hypertension and its sequelae, as well as the masking of inflammation must be closely monitored in pts receiving glucocorticoids.

*Abrupt cessation of glucocorticoid therapy can result in acute adrenal insufficiency b/c the hypothalamus and pituitary gland require a number of weeks to months to re-establish adequate ACTH production.
140. What are the names of the four glucocorticoids?
1. Prednisone
2. Prednisolone
3. Methylprednisolone
4. Dexamethasone
141. What is mycophenolic acid and mycophenolate mofetil?
Mycophenolic acid (MPA) is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), the rate limiting enzyme in the formation of guanosine.

B/c MPA has low oral bioavailability, it is usually administered in its prodrug form, mycophenolate mofetil (MFF), which has much higher oral bioavailability.
142. How does MPA and MMF work?
These drugs act primarily on lymphocytes. Inhibition of IMPDH by MPA reduces intracellular guanosine levels and elevates intracellular adenosine levels, with many downstream effects on lymphocyte activation and activity.

*Decreased guanosine levels lead to decreased expression of adhesion molecules involved in inflammation; also, it leads to a reduction in inducible NO synthase (iNOS), which leads to decreased NO production by neutrophils.
143. Mycophenolic acid and mycophenolate mofetil
MOA: Inhibitor of inosine monophosphate dehydrogenase (IMPDH), the rate limiting step in the formation of guanosine

PURPOSE: Solid organ transplantation, lupus nephritis, RA, pemphigus

ADVERSE: hypertension, peripheral edema, GI hemorrhage, leukopenia, myelosuppression, neutropenia, increased risk of infection, lymphoma, GI disturbance, headache

CONTRA: hypersensitivity to MPA or MMF, or to polysorbate 80 (IV formulation)

NOTES: Avoid concurrent administration of oral iron b/c it markedly reduces the bioavailability of MMF.
144. What is azathioprine (AZA)?
AZA was the first drug to be used for suppression of the immune system after transplantation. It is a prodrug of the purine analogue 6-MP, which is slowly released as AZA reacts nonenzymatically w/sulfhydryl compounds such as glutathione.

Although AZA does prolong organ graft survival, this drug is less efficacious than mycophenolate mofetil in improving the long-term survival of kidney allografts.

The slow release of 6-MP from AZA favors immunosuppression, while 6-MP itself is more useful as an antineoplastic drug.
145. What is methotrexate (MTX)?
MTX is a folate analogue used to treat malignancies and a wide variety of immune-mediated diseases, including RA and psoriasis. In addition, MTX is used for prevention of G vs. H disease.

The MOA by which MTX exerts its anti-inflammatory effect is uncertain, but does not appear to involve depletion of folate pools b/c the combo of MTX and folate is as effective as MTX alone in the treatment of RA.
146. How does MTX work as an anti-inflammatory and immunosuppressant?
MTX may act as an anti-inflammatory agent by increasing adenosine levels. Adenosine is a potent endogenous anti-inflammatory mediator that inhibits neutrophil adhesion, phagocytosis, and superoxide generation.

MTX has also been shown to cause apoptosis of activated CD4 and CD8 T cells, but not of resting cells.
147. What is leflunomide?
Leflunomide is an inhibitor of pyrimidine synthesis, specifically blocking the synthesis of UMP by inhibiting dihydroorotate dehydrogenase (DHOD). DHOD is a key enzyme in the synthesis of UMP, which is essential for the synthesis of all pyrimidines.

Lefunomide is approved for RA, but the drug has also shown significant efficacy in the treatment of other immune diseases.
148. Leflunomide
MOA: Inhibitor of pyrimidine synthesis by blocking DHOD.


ADVERSE: Hypertension, hepatotoxicity, interstitial lung disease, alopecia, diarrhea, rash

CONTRA: Pregnancy

NOTES: Leflunomide undergoes significant enterohepatic circulation, resulting in a prolonged pharmacologic effect. ***Cholestyramine may be administered to wash out leflunomide.
149. What is cyclophosphamide?
Cyclophosphamide is a highly toxic drug that alkylates DNA. B/c Cy has a major effect on B-cell proliferation but can enhance T-cell responses, the use of Cy in immune diseases is limited to disorders of humoral immunity, particularly SLE.

Adverse effects of Cy are severe and widespread, including leukopenia, cardiotoxicity, alopecia, and an increased risk of CA b/c of mutagenicity. The risk fo bladder CA is especially notable b/c Cy produces acrolein, which is concentrated in the urine.

Acrolein can be detoxed via administration of mesna.
150. What is cylcosporine (CsA)?
CsA is a specific inhibitor of T cell mediated immunity. CsA inhibits the production of IL-2 by activated T cells. CsA acts by binding to cyclophilin, and the CsA-cyclophilin complex binds to calcineurin in the NFAT pathway.

By inhibiting calcineurin-mediated NFAT dephosphorylation, CsA prevents translocation of NFAT to the nucleus and thereby suppresses IL-2 production.
151. Cyclosporine (CsA)
MOA: Binds to cyclophilin and the resulting complex inhibits the phosphatase activity of calcineurin, a cell-signaling protein that mediates T-cell activation.

PURPOSE: Keratoconjuctivitis sicca (topical cyclosporine)

ADVERSE: Nephrotoxicity, hypertension, neutrotoxicity, hepatotoxicity, infection, gingival hyperplasia, hyperlipidemia, hirsutism, GI disturbance

CONTRA: Active ocular infection

NOTES: Danazol and other androgens can increase serum CsA levels. Rifampin and St. John's wort reduce serum CsA levels.
152. What is tacrolimus?
AKA FK506, Tacrolimus is a more potent immunosupppresant drug than CsA; thought its structure differs from CsA, it acts by a similar MOA.

Tacrolimus is a macrocyclic triene that binds to FK-binding proteins, and the tacrolimus-FKBP complex inhibits calcineurin. Tacrolimus also inhibits IL-3, IL-4, IFN-y, and TNF-a production.
153. Tacrolimus
MOA: Binds to FK-binding protein and the tacrolimus-FKBP complex inhibits calcineurin.

PURPOSE: Organ transplantation, atopic dermatitis (topical)

ADVERSE: Nephrotoxicity, hypertension, prolonged QT interval, hyperglycemia, lymphoma infection, alopecia, GI disturbance , anemia, leukocytosis, thrombocytopenia, headache, insomnia, paresthesia, tremor, skin irritation.

CONTRA: Hypersensitivity to hydrogenated castor oil (IV formulation)

NOTES: Topical tacrolimus is used widely to treat atopic dermatitis and other eczematous dermatitis. St. Johns wort markedly reduces serum tacrolimus levels.
154. What is sirolimus?
Sirolimus, AKA rapamycin, is a macrocyclic triene that is used to prevent and treat organ rejection.

It also binds to FKBP, but the sirolimus-FKBP complex does not inhibit calcineurin; instead, it blocks the IL-2 receptor signaling required for T-cell proliferation.

Sirolimus-FKBP binds to and inhibits mTOR, a regulator of protein translation, and thus it arrests cell division in the G1 phase.
155. Sirolimus
MOA: Sirolimus binds to FKBP, and the resulting sirolimus-FKBP complex inhibits mTOR, a regulator of protein translation

PURPOSE: Organ transplantation, coronary artery disease (cardiac stents)

ADVERSE: Hypertension, peripheral edema, thromboembolic disorder, hyperlipidemia, hepatotoxcitiy, anemia, thrombocytopenia, arthralgia, asthenia, headache.

CONTRA: Hypersensitivity

NOTES: Sirolimus-eluting stents are also used in the treatment of coronary artery disease. Coadministration w/voriconazole markedly increases serum sirolimus level.
156. Etanercept
MOA: Etanercept is a soluble TNF receptor dimer that binds to both TNF-α and TNF-β.

PURPOSE: RA, juvenile RA, psoriasis, psoriatic arthritis, ankylosing spondylitis

ADVERSE: Myelosuppression, heart failure, optic neuritis, reactivation of tuberculosis, increased risk of infection, demyelinating disease of CNS, injection site reaction, URI, abdominal pain, vomiting.

CONTRA: Sepsis and heart failure

NOTES: *All patients should undergo screening for TB before therapy. Any patient developing an infection while taking a TNF inhibitor should undergo eval and aggressive antibiotic treatment.
157. Infliximab and adalimumab
MOA: Infliximab is a partially humanized mouse antibody against human TNF-α; adalimumab is a fully humanized IgG1 antibody against TNF-α.

PURPOSE: RA, Crohn's disease (infliximab), UC (infliximab), ankylosing spondylitis (infliximab), psoriatic arthritis (adalimumab)

ADVERSE: Same as etanercept

CONTRA: Sepsis and heart failure

NOTES: Certolizumab pegol, a pegylated TNF-α antibody, is currently is late stage clinical trials.
158. What is anakinra?
Anakinra is a recombinant form of IL-1ra, and is approved for use in RA. It has modest effects on pain and swelling but significantly reduces bony erosions, possibly b/c it decreases osteoclast production and blocks IL-1 induced metalloproteinase release fro synovial cells.
159. Anakinra
MOA: Recombinant IL-1 receptor antagonist


ADVERSE: Neutropenia, increased risk of infection

CONTRA: Hypersensitivity to anakinra or E. coli derived proteins

NOTES: Reduces bony erosions possibly by decreasing metalloproteinase release from synovial cells.
160. What is anti-thymocyte globulin (ATG)?
ATG is a preparation of antibodies induced by injecting rabbits w/human thymocytes. The rabbit antibodies are polyclonal and probably target many epitopes on human T cells.

B/c ATG targets essentially all T cells, ATG treatment results in broad immunosuppression that can predispose to infection.
161. . Anti-thymocyte globulin (ATG)
MOA: Polyclonal antibodies against human T-cell epitopes

PURPOSE: Organ transplantation

ADVERSE: Cytokine release syndrome (fever, shivering, myalgia, headache), hypertension, anemia, leukopenia, thrombocytopenia, increased risk of infection.

CONTRA: Acute viral illness, history of allergy or anaphylaxis to rabbit proteins

NOTES: ATG treatment can result in a broad immunosuppression that can lead to infection.
162. What is OKT3?
*OKT3 is a mouse monoclonal antibody against human CD3*, one of the cell-surface signaling molecules important for activation of T-cell receptor.

Treatment with OKT3 depletes the available pool of T cells via antibody-mediated activation of complement and clearance of immune complexes.
163. OKT3
MOA: Mouse monoclonal antibody against human CD3, a signaling molecule important for T cell receptor mediated cell activation

PURPOSE: Organ transplantation

ADVERSE: *Cytokine release syndrome (fever, shivering, myalgia, headache), hypertension, anemia, leukopenia, thrombocytopenia, increased risk of infection.

CONTRA: Anti-mouse antibody titers greater than 1:1000; heart failure, seizures, pregnancy or breastfeeding, uncontrolled hypertension.
164. What is rituximab (anti-CD20 mAb)
Rituximab is a partially humanized anti-CD20 antibody. CD20 is expressed on the surface of all mature B cells, and administration of rituximab causes profound depletion of circulating B cells.

Originally approved for the treatment of CD20+ non-Hodgkin's lymphoma, rituximab has also been approved for use in RA refractory to TNF-a inhibitors.
165. Daclizumab and basiliximab
MOA: Antibodies to CD25, the high-affinity IL-2 receptor

PURPOSE: Organ transplantation

ADVERSE: *Cytokine release syndrome (fever, shivering, myalgia, headache), hypertension, anemia, leukopenia, thrombocytopenia, increased risk of infection.

CONTRA: Hypersensitivity
166. Alemtuzumab
MOA: Antibody to Campath-1 (CD52), an antigen expressed on most mature lymphocytes and some lymphocyte precursors

PURPOSE: B-cell chronic lymphocytic leukemia

ADVERSE: *Cytokine release syndrome (fever, shivering, myalgia, headache), hypertension, anemia, leukopenia, thrombocytopenia, increased risk of infection.

CONTRA: Active systemic infection, underlying immunodeficiency.
167. Alefacept
MOA: LFA-3Fc fusion protein that interrupts CD2/LFA-3 signaling by binding to T-cell CD2, leading to inhibition of T-cell activation.

PURPOSE: Psoriasis

ADVERSE: *Cytokine release syndrome (fever, shivering, myalgia, headache), hypertension, anemia, leukopenia, thrombocytopenia, increased risk of infection.

CONTRA: HIV infection, low CD4 T-cell count

NOTES: Pts taking alefacept may have an increased risk of serious infection and malignancy, primarily skin CA.
168. Abatacept
MOA: CTLA-4 analogues fused to an IgG1 constant region; by forming a complex w/cell-surface B7 molecules, the drug prevents delivery of a costimulatory signal and the T cell develops anergy or undergoes apoptosis.

PURPOSE: RA refractory to MTX or TNF-a inhibitors

ADVERSE: Exacerbation of COPD, increased susceptibility to infection, nausea, headache, UTI

CONTRA: Hypersensitivty

NOTES: Abatacept should not be administered concurrently w/TNF-a inhibitors or anakinra due to increased risk of infection.
169. What is belatacept?
Belatacept is a close structural congener of abatacept that has increased affinity for B7-1 and B7-2.

In a large clinical trial, belatacept was as effective as cyclosporine at inhibiting acute rejection in renal transplant recipients.
170. Efalizumab
MOA: Monoclonal antibody against LFA-1 that inhibits the LFA-1/ICAM-1 interaction and thereby limits T-cell adhesion, activation, and migration to sites of inflammation.

PURPOSE: Chronic plaque psoriasis

ADVERSE: Increased risk of serious infection, immune-mediated thrombocytopenia, immune-mediated hemolytic anemia, inluenza-like symptoms, acne, lymphocytosis, elevated ALKPHOS, antibody formation to efalizumab

CONTRA: Hypersensitivity

NOTES: Symptoms of psoriasis return promptly after discontinuation
171. Natalizumab
MOA: Monoclonal antibody against α4 integrin that inhibits immune cell interaction w/cells expressing VCAM-1 and MAdCAM-1

PURPOSE: Multiple sclerosis

ADVERSE: Cholelithiasis, progressive multifocal leukoencephalopathy, depression, pneumonia, rash, arthralgia, headache, fatigue, UTI, lower respiratory tract infection

CONTRA: History of progressive multifocal leukoencephalopathy (PML) or existing PML

NOTES: PML is a rare demyelinating disorder caused by infection w/JC virus.
172. Eculizumab
Eculizumab is a humanized monoclonal antibody against C5, a complement protein that mediates late steps in complement activation and triggers assembly of the MAC.

In clinical trials, eculizumab is used to treat paroxysmal nocturnal hemoglobinuria.
173. How does carbon monoxide cause poisoning?

Which way does the Hgb O₂ curve shift?
CO causes tissue hypoxia by binding more strongly to the heme iron in Hgb than does O₂, thereby reducing the transport of oxygen in the blood. In addition, carboxyhemoglobin shifts the dissociation cure for oxyhemoglobin to the left, impeding the dissociation of O₂.
174. What is the difference between hydrofluoric acid and hydrochloric acid?
HF causes milder skin burns than an equivalent amt of HCl. However, once HF reaches deeper tissue, it destroys the calcified matrix of bone. In addition to the direct effects of the acid, the release of calcium stored in bone can cause life-threatening cardiac arrhythmias. For this reason, HF can be more dangerous than an equivalent amt of HCL.
175. What are three characteristics that determine the extent of tissue damage?
1. The compounds identity
2. Its concentration/strength
3. Its buffering capacity, or ability to resist change in pH or redox potential
176. How are organophosphate insecticides poisonous?
Insecticides derived from phosphoric or thiophosphoric acid include parathion, malathion, diazinon, fenthion, and chlorpyrifos.

These compounds are AChE inhibitors due to their ability to phosphorylate AChE at its esteratic active site.

Inhibition of AChE, and consequent accumulation of ACh at cholinergic junctions in nerve tissue and effector organs, produces acute muscarinic, nicotinic, and CNS effects such as bronchconstriction, increased bronchial secretions, salivation, lacrimation, sweating, nausea, vomiting, diarrhea, and miosis, as well as twitching, fasciculations, muscle weakness, cyanosis, and elevated BP.

Symptoms usually occur w/in minute or hours of exposure and resole w/in a few days in nonlethal poisonings.
177. What are the pyrethroid insecticides and how are they poisonous?
Pyrethroid insecticides, such as permethrin, deltamethrin, cypermethrin, and cyfluthrin, are semisynthetic chemicals that are structurally related to the naturally occurring pyrethrins found in chrysanthemum flowers.

The pyrethroids have very high affinity for plasma membrane sodium channels, and, while they do not alter activation of sodium currents by membrane depolarization, they significantly delay terminal of the action potential.
178. What are the two classes of pyrethroids?
1. Type I pyrethroids do not contain a cyano group, produce shorter duration sodium tail currents and repetitive discharges, and cause a tremor (T) syndrome in mammals that can include fine tremor, increased response to stimuli, and hyperthermia.

2. Type II pyrethroids usually contain a cyano group, produce a longerduration sodium tail current and stimulus dependent nerve depolarization and block, and cause a choreoathetosis-with-salivation syndrome that may include sinuous writhing and salivation, coarse tremor, clonic seizures, and hypothermia.
179. How is the Amanita phalloides toxic to humans?
The amatoxins bind strongly to RNA polymerase II, greatly slowing RNA and protein synthesis and leading to hepatocyte necrosis.

COnsumpation of Amanita species can thus cause severe liver dysfunction, even hepatic and renal failure and death. Initial symptoms of poisoning such as abdominal pain, nausea, severe vomiting and diarrhea, fever and tachycardia may occur 6-24 hours after consumption of the mushrooms. There is no antidote.
180. What is cerulide?
B/ cereus is a common contaminant of cooked rice. It produces several toxins that cause vomiting and diarrhea. Of particular concern is the production of cerulide, a small, cyclic peptide that stimulates intestinal 5-HT3 receptors, resulting in emesis.
181. What are saxitoxins?
Most algal toxins are neurotoxic and heat stable, so cooking leaves the toxins intact.

Algal toxins such as saxitoxins are a group of approx 20 heterocyclic guanidines that bind w/high affinity to the voltage-dependent sodium channel, thus inhibiting neuronal activity and cause tingling an numbness, loss of motor control, drowsiness, incoherence, and with sufficient doses, respiratory paralysis.
182. How is jimson weed toxic?
All parts of the plant are toxic, but the seeds and leaves in particular contain atropine, scopolamine, and hyoscyamine. These compounds are rapidly absorbed and produce anticholinergic symptoms such as mydriasis, dry flushed skin, agitation, tachycardia, hyperthermia, and hallucinations.
183. What is the mnemonic for anticholinergic effects?
"Blinds as a bat; dry as a bone; red as a beet, mad as a hatter, and hot as a hare"
184. What are psoralen isomers (furocoumarins)?
These substances come from pants such as parsley, hogweed, figs,, etc... Psoralen isomers can be absorbed into the skin after contact. Subsequent exposure to UV-A radiation can excite furocoumarins, which then form DNA-damaging adducts in epidermal tissue.

W/in 2 days, burning, redness and blistering are observed in areas of contact w/the plant and light; after healing, hyperpigmentation may persist.
185. What are 3 mechanisms of alcoholic hepatotoxicity?
1. Associated w/a nutritional deficiency, which leads to a hypermetabolic state and increased oxygen demand on the liver.
2. The metabolism of alcohol generates NADH and NADPH, which shift the redox potential of the hepatocyte. The altered redox potential leads to the increased production of lactic acid and uric acid and to hypoglycemia.
3. Ethanol metabolism produces harmful ROS, including acetaldehyde, and hydroxyl radicals, superoxide anions, and hydrogen peroxide (produced by the action of the enzyme P450 2E1).
186. How is lead toxic?
Lead causes a disruption of the blood-brain barrier, allowing both lead and other potential neurotoxins to reach the CNS. There, lead can block voltage-dependent calcium channels, interfere w/neurotransmitter function, and most importantly interfere w/cell-cell interactions in the brain.

Overt lead encephalopathy can occur, which results in lethargy, vomiting, irritability, dizziness, and progresses to coma and death if untreated.
187. How is lead toxic to Hgb?
Lead interferes w/the synthesis of hemoglobin at multiple steps, causing a microcytic, hypochromic anemia. Specifically, lead inhibits the action of delta-aminolevulinic acid dehydratase (ALA-D), which catalyzes the synthesis of porphobilinogen, a heme precursor. Lead also inhibits the incorporation of iron into the porphyrin ring.
188. What is cadmium?
Cadmium dusts and fumes may be encountered in various occupations. It has a particular toxicity to the kidney following inhalation exposure.

Abnormal renal function, consisting of proteinuria and decreased GFR occurs. The proteinuria consists of LMW proteins that are normally filtered but in this case they are not. Cadmium exposed workers also have a higher rate of kidney stone formation, perhaps due to disruption of calcium metabolism as a consequence of renal damage.
189. What is metallothionein, and how is it involved w/cadmium?
Metallothionein may be involved in cadmium related kidney damage; this cadmium-binding protein, which is synthesized in the liver and kidney, appears both to facilitate transport of cadmium to the kidney and to promote retention of cadmium in the kidney.
190. What are the 3 strategies used alter the toxicokinetics of a poison so as to minimize exposure?
1. Decrease the absorption
2. Preventing toxication of a benign compound
3. Increasing the metabolism or elimination of the toxin
191. What is the antidote to beta-adrenergic antagonist overdose?

How does it work?
Glucagon; this is used to increase HR and BP and parenteral fluids to treat hypotension.

Glucagon increases cAMP in cardiac cells by stimulating glucagon receptor-mediated activation of adenylyl cyclase. Glucagon is also locally metabolized to a mini-glucagon fragment that increases intracellular calcium by stimulating phospholipase A2.
192. What is used to treat salicylate poisoning?
Sodium bicarb is administered both to maintain a normal serum pH and to alkalinize the urine. Alkalinizing the urine promotes the renal excretion of salicylate.
193. What is the most common method of inducing emesis?

How does it work?
Ipecac syrup. Locally, it irritate the GI tract, while centrally, it activates the chemoreceptor trigger zone in the area postrema of the brain.
194. What is the antidote to antifreeze poisoning?
B/c ethanol is also metabolized by alcohol dehydrogenase, it can function as a competitive inhibitor for both methanol and ethylene glycol.

More recently, fomepizole has been employed instead of ethanol b/c it is not itself metabolized by alcohol dehydrogenase and does not cause symptoms of inebriation.
195. What is used to treat cyanide poisoning?
Treated w/a kit containing amyl nitrite or sodium nitrite and sodium thiosulfate.

The nitrates act by oxidizing Hgb to methemoglobin to provide a substrate that can compete w/cytochrome c oxidase for cyanide molcules. The methemoglobin-bound cyanide is then oxidize to the relatively nontoxic thiocyanate by the enzyme rhodanese.

The addition of thiosulfate provides a ready source of sulfur for the detox reaction and enhances cyanide metabolism.
196. What is ion trapping?
Ion trapping involves alkalinization of the urine to enhance renal clearance of a weakly acidic toxin.

In ion trapping, the neutral form of the toxin is filtered thru the glomerulus, and this form becomes deprotonated in the alkalinzed urine. The ionized form of the toxin is not reabsorbed and is therefore excreted in the urine.

Clinically, ion trapping is accomplished by administering bicarb to the patient and titrating to a urine pH of 7.5-8.5. This technique is especially useful in the elimination of salicylates and phenobarbital.
197. What is hemodialysis used for?
Hemodialysis is generally useful for small molecules that have a small volume of distribution, are relatively water soluble, and are not highly bound to plasma proteins (which cannot cross the dialysis membrane).
198. What is hemofiltration used for?
B/c the plasma is exposed to a filter rather than a semipermeable membrane, larger molecules can be clears w/hemofiltration than w/hemodialysis
199. What is hemoperfusion?
Blood is passed thru a cartridge where ti comes in contact w/an ion-exchange resin or activated charcoal that can adsorb the toxin.

B/c of the direct contact between blood and the adsorbent material, hemoperfusion poses a risk of thrombosis and it could deplete plasma of calcium and magnesium.
200. What is a chelator?

What are the requirements for chelators?
A chelator is a multidentate structure w/multiple binding sites. Binding the metal at multiple sites shifts the equilibrium constant in favor of metal ligation. High-affinity metal-ligand binding is critical b/c the chelatory must compete w/tissue macromolecules for binding.

In addition, the chelator should be nontoxic and water soluble and readily cleared.

Finally, an ideal chelator should have a low binding affinity for endogenous ions such as calcium.
201. What are the most important heavy metal chelators?
EDTA, which can be used to bind lead;

Dimercaprol, which binds gold, arsenic, lead, and mercury to its two thiol groups

Succimer which as supplanted dimercaprol for the removal of lead, cadmium, mercury, and arsenic.

Deferoxamine is used for the removal of toxic levels of iron.

Removal of copper, typically in patients w/Wilson's disease, is accomplished w/penicillamine, or for patients who do not tolerate penicillamine, tientine.
202. What is the treatment for digoxin overdose?
Digoxin immune Fab. It is an antibody that includes on the Fab fragment of the immunoglobulin.

This treatment is used in cases where the patient is experiencing signs or symptoms due to toxic plasma levels of the drug.
203. What is an inherent danger in the use of antibodies as inactivators?
One inherent danger in the use of antibodies as inactivators is the risk of developing serum sickness, a type III hypersensitivity reaction.

Both antivenins and digoxin immune Fab can cause serum sickness.
204. What is the treatment for opioid overdose?
An opioid overdose can be treated w/naloxone, a pharmacologic antagonist of the opioid receptor. Naloxone has a rapid onset of action is is highly potent.
205. What is the treatment for benzodiazepine overdose?
Flumazenil is a pharmacologic antagonist at the GABA receptor an dis used to treat benzodiazepine overdose and zolpidem overdoses.
206. What is the treatment for AChE inhibition?
Atropine. By antagonizing the muscarinic ACh receptor, atropine restores cholinergic balance and prevents bronchocontriction, the most common cause of death in patients with exposure to AChE inhibitors.
207. What is the treatment for jimson weed poisoning (AChE excess)?
Treatment involves the administration of physostigmine which blocks AChE to increase cholinergic tone.

*It should be noted that atropine, an anticholinergic agent, is the DOC for organophosphate poisoning of AChE, whereas an AChE inhibitor is the DOC for poisoning w/an anticholinergic toxin.
208. What is the treatment for CO and cyanide poisoning?
Treatment invovles displacing the small molecule from its heme target. For CO poisoning, high concentrations of oxygen are administered. For severe poisonings, a pt may be placed in a hyperbaric oxygen chamber.

Cyanide cannot be displaced from oxygen. However, by oxidizing Hgb to its ferric state with amyl nitrite or sodium nitrite, a competitor for cyanide is generated. Afterwards, methylene blue can reduce the ferric iron to its ferrous state.
209. What is the treatment of acute organophosphate poisoning?
Acute treatment for organophosphate poisoning involves restoration of the active site of the enzyme. While the administration of atropine can block the excess ACh at muscarinic receptors, it cannot restore the enzymatic function of AChE.

However, pralidoxime can enhance the hydrolysis of the serine-phosphate bond between the organophosphate and AChE.