Module 4 Section 4 (Coagulation)

Question 1

What is hemostasis?

Answer 1

Hemostasis is a finely regulated process that causes bleeding to stop, while maintaining the flow of blood within the vessel.

Question 2

What occurs after an injury of a vessel?

Answer 2

Following injury of a vessel, a clot or plug is formed at the site of injury to prevent excess blood loss.

Once the injury has been repaired, the clot must be removed, so that normal tissue perfusion with blood can resume.

Question 3

What represents the breakdown of the normal hemostatic mechanism?

Answer 3

Excessive bleeding or excessive thrombi (clot) formation are pathological conditions and represent a breakdown of the normal hemostatic mechanism.

Question 4

What are coagulation disorders?

Answer 4

Coagulation disorders include any disruption of the body’s ability to control blood clotting and are often characterized by excessive bleeding.

Question 5

When injury to the vessel wall occurs, cells lining the damaged blood vessels release chemicals that start the clotting process. The blood coagulation cascade is characterized by 3 major steps. What are they?

Answer 5

1) Vasoconstriction: after the vessel is injured, it goes into spasm and vasoconstricts, restricting blood loss.
2) Formation of a platelet plug: platelets adhere to collagen fibrils on the injured vessel with the help of von Willebrand factor. The platelets aggregate together and adhere to the site of injury, forming a plug.
3) Blood coagulation: simultaneously, the coagulation pathway is activated, resulting in the formation of fibrin strands that turn the platelet plug into a more stable blood clot, thus completing the coagulation process.

Question 6

What is the coagulation cascade?

Answer 6

The coagulation cascade is a complex process involving a number of clotting factors.

These clotting factors normally exist in the blood in inactive forms.

During the process of coagulation, these clotting factors are activated, and hence go from an inactivated clotting factor (e.g. factor X), to an active clotting factor (e.g. factor Xa).

Question 7

What are the 2 clotting pathways?

Answer 7

Extrinsic Pathway: it’s activated by external trauma, and begins when damaged tissue releases tissue factor (TF), which binds to factor VIIa.

• This complex in turn activates factor X to Xa. Factor Xa, combined with factor Va, converts factor II (prothrombin) to factor IIa (thrombin).
• Thrombin then converts fibrinogen to fibrin, completing the clot.

Intrinsic Pathway: it’s activated by internal trauma to blood vessels, and involves factors XII, XI, and IX.
- The result of this pathway is also activation of factor X, which then follows the same process as occurs in the extrinsic pathway ultimately forming fibrin, completing the clot.

Question 8

What is fibrinolysis?

Answer 8

Fibrinolysis is the enzymatic process that dissolves the fibrin clot.

• It occurs concomitantly with coagulation and controls the size and spread of the fibrin clot.
• It also completely removes the clot once the vessel has been repaired, allowing normal blood flow to the affected area.

Tissue plasminogen activator (t-PA) activates plasminogen to plasmin, which breaks down the fibrin clot.
- Tissue plasminogen activator and plasmin are inhibited once the fibrin clot is dissolved.

Question 9

Regulation of the coagulation pathway occurs at various phases - either by enzymatic inhibition or modulation of cofactor activity. One particular regulatory component of the coagulation cascade involves antithrombin III. What is it?

Answer 9

Antithrombin III is a small protein that functions as an endogenous anticoagulant.

• It neutralises a number of the active cofactors in clotting (e.g. thrombin, fibrin, Xa).
• Antithrombin III keeps the balance between bleeding and formation of intravascular clots. It has an important role in the action of some anticoagulants.

Question 10

What is thromboembolic disease?

Answer 10

Thromboembolic disease is characterized by hypercoagulable states, which can manifest as deep vein thrombosis, pulmonary embolism, or coronary artery disease.

Question 11

What conditions can result in intravascular clot formation?

Answer 11

A number of conditions can result in intravascular clot formation that require pharmacological intervention.

• Primarily, these conditions include genetic factors or acquired defects in the clotting mechanisms.
• Secondarily, intravascular clot formation can occur as a result of infection, cancer, or trauma. Some drugs also predispose an individual to thrombosis (e.g. oral contraceptives).

Question 12

What are the 2 types of thrombi?

Answer 12

1) Arterial thrombi: these are made up of mainly platelets (white thrombi) and form in high flow areas. Arterial thrombi restrict the flow of blood to the tissue or organ supplied by that artery, leading to tissue ischemia.

2) Venous thrombi: these clots tend to contain more fibrin (red thrombi).
- They form in large vessels, and as the clot continues to form, a tail of loose fibrin develops.
- This portion of the clot can dislodge and move to other areas of the body, and may become trapped in the arteries of other organs such as the lung, heart, or brain, leading to a pulmonary embolism, heart attack, or stroke, respectively.

Question 13

Thromboembolic diseases can be treated using three different classes of antithrombotic agents. What are they?

Answer 13

• Anticoagulants: drugs that prevent or reduce coagulation within a blood vessel by inhibiting the coagulation cascade. Also known as blood thinners.

Antiplatelets: drugs that decrease the aggregation of platelets within a blood vessel.

Thrombolytics: drugs that breakdown a clot that has already formed. Also known as clot busters.

Question 14

What is the aim of anticoagulant therapy?

Answer 14

The aim of anticoagulant therapy is to prevent the formation of intravascular thrombi, while minimizing the tendency to bleed.

Question 15

What are the adverse effects of all anticoagulants?

Answer 15

All anticoagulants have bleeding as a major adverse effect.

- Anticoagulants do not alter the existing thrombi, but rather prevent further formation of thrombi.

Question 16

What are the 2 main anticoagulant therapeutics commonly used to prevent or reduce coagulation of blood, thus prolonging the clotting time?

Answer 16

• Thrombin inhibitors

- Warfarin

Question 17

What are the 3 main types of thrombin inhibitors?

Answer 17

1) Heparin and low molecular weight heparins
2) Oral Factor Xa Inhibitors
3) Direct Thrombin (Factor IIa) Inhibitors

Question 18

What is heparin and how does it work?

Answer 18

Heparin is a natural substance occurring in mast cells of mammalian species.

• It is often extracted from pig intestine for pharmacological use.
• Heparin has a molecular weight of about 15,000 g/mol.
• The weight of low molecular weight heparins is 5000 g/mol.
• Both of these agents must be given by injection.

They indirectly inhibit thrombin (factor IIa). Specifically, these drugs bind to antithrombin III, enhancing the ability of antithrombin III to inhibit the clotting factors Xa and IIa.

• In the case of fondaparinux, only Xa is inhibited. The heparins accelerate the inhibition of Xa and IIa by antithrombin III up to 1000-fold.
• The response to the heparins is immediate. By removing clotting factors Xa and IIa, anticoagulation is achieved rapidly.

A test that determines the time required for the blood to clot must be determined. This test allows for the adjustment of the dose of heparin.

Question 19

What are oral factor Xa inhibitors and how do they work? Provide an example

Answer 19

The heparins must be given by injection, which is inconvenient and decreases compliance, therefore a need to develop inhibitors of thrombin that could be administered orally was evident.

• The solution was oral factor Xa inhibitors.
• Recent clinical trials suggest that these drugs are as effective as the heparins.
• In addition, the effect of these drugs does not have to be monitored.

It indirectly inhibits thrombin (factor IIa).

Ex: Rivaroxaban is an oral factor Xa inhibitor that is approved for the prevention of venous thromboembolism following hip and knee surgery.

Question 20

What are direct thrombin (factor IIa) inhibitors and how do they work?

Answer 20

Leeches have been used as a form of blood-letting for centuries.
- The saliva of the leech contains an anticoagulant known as hirudin, an inhibitor of thrombin (factor IIa).

Hirudin is available as a drug from recombinant sources and is marketed as lepirudin. Unlike the heparins, lepirudin does not require antithrombin III for activity, but inhibits thrombin action directly.

• Lepirudin is administered parentally, and its effect has to be monitored as is done with the heparins.
• However, oral direct thrombin inhibitors, such as dabigatran, do exist, removing the need for monitoring.
• These drugs are used if the patient cannot tolerate the heparins.

Question 21

True or false: leeches are still used in medicine today to prevent clotting and increase blood flow, specifically for skin grafts or reattachment of limbs.

Answer 21

True

Question 22

What is warfarin and how does it work?

Answer 22

Warfarin is a widely prescribed drug, as it is an anticoagulant that can be administered orally, is relatively inexpensive, and is effective.

The mechanism of action of warfarin is the inhibition of the vitamin K dependent clotting factors VII, IX, X, and II.
- Vitamin K is a cofactor in the synthesis of these clotting factors.

Question 23

The structures of warfarin and vitamin K are similar, allowing warfarin to bind to and inhibit the enzyme that activates vitamin K. What happens when this occurs?

Answer 23

As a result, the vitamin K is trapped in the un-activated epoxide form, and therefore less active vitamin K is available to make the vitamin K-dependent clotting factors.
- Since warfarin inhibits the synthesis of clotting factors, the onset of response is delayed for 8 to 12 hours, as time is required for the existing clotting factors to be utilized.

Question 24

What are the disadvantages of warfarin?

Answer 24

1) It can cross the placenta and can cause bleeding in the fetus; it is also teratogenic.
2) The degree of anticoagulation must be carefully monitored, especially as the dose is titrated to the appropriate effect.
3) The response to warfarin is modified by many other drugs, herbals, and food.

Question 25

What are the clinical uses of anticoagulants?

Answer 25

1) Inherited disorders of coagulations, where the natural anticoagulant system has some form of deficit.

2) Acquired disease. A number of disorders (e.g. atrial fibrillation) put the person at a high risk for the formation of venous thrombi.
- Long-term use of warfarin reduces the incidence of thrombotic events.
- Warfarin is also used in patients with artificial heart valves, as they are at a higher risk for thrombosis.

3) Prophylactic use during hip and knee replacement surgeries to prevent thrombotic complications.
- Usually a low molecular weight heparin is administered subcutaneously.

4) Treat overt thromboembolic disease.
- Venous thrombosis is treated initially with heparin or low molecular weight heparin for the first five to seven days, and then the therapy is switched to the oral agent, warfarin.

Question 26

Recall that platelet aggregation is the initial step in arresting bleeding after injury to a vessel. Platelets also participate in several pathological conditions, where formation of intravascular thrombi has a key role. What are they?

Answer 26

These disorders are myocardial infarction, stroke, and peripheral vascular disease.

Prevention of thrombi formation with drugs reduces the incidence of vascular events and improves overall survival.

Question 27

Three triggers for platelet aggregation can be targets for drug action. What are they?

Answer 27

1) Membrane receptors (i.e. glycoprotein IIB/IIIA receptors) on the exterior of the platelet that respond to norepinephrine, thrombin, and some of the prostaglandins, initiating platelet aggregation.
2) The platelet produces adenosine diphosphate (ADP) and prostaglandins (among other compounds) that can interact with ADP and prostaglandin receptors on the surface of the platelet.
3) The platelet produces thromboxane A2, cyclic AMP, and calcium ions that act inside the platelet to promote platelet adherence.

Question 28

What are the antiplatelet drugs that target those triggers and are used to treat thromboembolic diseases?

Answer 28

1) COX-1 Inhibitors
2) ADP receptor inhibitor
3) Platelet Glycoprotein IIB/IIIA Receptors

Question 29

What are COX-1 Inhibitors and how do they work? Provide an example

Answer 29

In platelets, the major prostaglandin produced is thromboxane A2 (TXA2). It is an inducer of platelet aggregation and a potent vasoconstrictor.
- Aspirin reduces the formation of TXA2 by irreversibly inhibiting cyclooxygenase-1 (COX-1), the enzyme system responsible for the formation of the prostaglandins.

Ex: Aspirin is utilized as an antithrombotic agent in a person at risk for stroke, heart attacks, and ischemic vascular disease.
- Primary prevention of vascular events is undoubtedly the major use of aspirin today.

Question 30

What are ADP receptor inhibitors and how do they work? What are some clinical uses? Provide an example

Answer 30

These compounds (e.g. ticlopidine and clopidogrel) block platelet aggregation by inhibiting the ADP dependent activation of platelets. 
- The drugs irreversibly block the ADP receptors on the platelets. 

Clinical use:
- Some clinical uses of this class of drugs include prevention of recurrent stoke, reduction or prevention of myocardial infarct, ischemic stroke, and following vascular surgeries such as stent replacement. 

Ex: Clopidogrel, sold as the brand name Plavix among others, is an antiplatelet medication that is used to reduce the risk of heart disease and stroke in those at high risk.

Question 31

What are Platelet Glycoprotein IIB/IIIA Receptors and how do they work? What are some clinical uses? Provide an example

Answer 31

The third group of drugs available for inhibiting platelet function block the membrane receptors GPIIb/IIIa on the exterior of the platelet, inhibiting platelet aggregation.

• Most of these drugs are biologicals.
• Drugs in this class are approved to prevent coronary vessel occlusion in patients undergoing coronary angioplasty (bypass surgery).

Ex: Abciximab is a glycoprotein IIb/IIIa receptor inhibitor. It is mainly used during and after coronary artery procedures like angioplasty to prevent platelets from sticking together and causing thrombus (blood clot) formation within the coronary artery.

Question 32

True or false: once an intravascular thrombus has formed, anticoagulants and antiplatelets cannot remove the clot, they can only prevent further clotting.

Answer 32

True

However, the administration of plasmin activators can remove the clot.

Question 33

What at thrombolytic drugs used for? Give an example

Answer 33

Thrombolytic drugs reduce the mortality of acute myocardial infarction (i.e. a heart attack due to blockage of a coronary artery by a clot), with the greatest benefit occurring when the thrombolytic drug is given early.

Ex: administering a thrombolytic within six hours of symptomatic onset of an acute heart attack results in the greatest benefit.

Question 34

What 2 commonly used thrombolytic drugs cause the breakdown of fibrin by increasing the formation of plasmin?

Answer 34

Two commonly used drugs are streptokinase, a protein that catalyzes the conversion of plasminogen to plasmin, and alteplase, a human tissue plasminogen activator (t-PA) prepared by recombinant technologies. These drugs cause the breakdown of fibrin by increasing the formation of plasmin.

Streptokinase and alteplase are indicated for pulmonary embolism, severe deep vein thrombosis, and acute myocardial infarct.

• t-PA is also approved for use in ischemic stroke caused by a clot.
• The drugs are used to break up a clot in an occluded vessel that caused the stroke or infarct, with the aim of allowing reperfusion of the affected tissue.
• The sooner a clot is dissolved after it is formed, the more favourable the clinical outcome.

Question 35

What is the mechanism of action of each of the listed antithrombotic agents?

a) Thrombolytics
b) Antiplatelets
c) Anticoagulant

Answer 35

a) Thrombolytics = breaks down a clot that has already formed.
b) Antiplatelets = prevents platelets from aggregating and forming a clot
c) Anticoagulant = slows down the formation of a clot

Question 36

Abnormal hemostasis can also result in excessive bleeding. What can lead to this?

Answer 36

Abnormal or excessive bleeding can occur due to major traumas, surgeries, or conditions such as hemophilia.

Question 37

What is hemophilia?

Answer 37

Hemophilia is a congenital or acquired bleeding disorder due to coagulation factor deficiency.

• Hemophilia A is deficient in factor VIII.
• Hemophilia B is deficient in factor IX.
• Hemophilia C is deficient in factor XI.

Question 38

What is a common treatment for abnormal bleeding?

Answer 38

One common treatment for abnormal bleeding is Vitamin K.

• Clotting factors VII, IX, X, and II are vitamin K dependent.
• Vitamin K is used clinically in cases of vitamin K deficiency or in warfarin overdosage, and can be administered either orally or intravenously

Question 39

What is administered in the case of hemophilias?

Answer 39

In the case of hemophilias, where specific coagulation factors are deficient, concentrated plasma fractions containing the missing factors are administered to the patient.
- Concentrated plasma fractions, specifically factor VIII or factor IX, may also be used to stop bleeding after surgery ormajor trauma.

Question 40

Which one of the following statements regarding the mechanism of action of heparin is correct?

a) Heparin inhibits prothrombin directly
b) Heparin accelerates the rate of conversion of plasminogen to plasmin
c) Heparin binds to antithrombin III, and enhances the action of antithrombin III
d) Heparin can inhibit cyclooxygenase, and prevent the formation of thromboxane A2.

Answer 40

c) Heparin binds to antithrombin III, and enhances the action of antithrombin III

Question 41

Which one of the following drugs will most likely be used for abnormal/excessive bleeding?

a) Vitamin K
b) Aspirin
c) Heparin
d) Streptokinase

Answer 41

a) Vitamin K