Module 4 Section 4 (Coagulation) Flashcards
What is hemostasis?
Hemostasis is a finely regulated process that causes bleeding to stop, while maintaining the flow of blood within the vessel.
What occurs after an injury of a vessel?
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.
What represents the breakdown of the normal hemostatic mechanism?
Excessive bleeding or excessive thrombi (clot) formation are pathological conditions and represent a breakdown of the normal hemostatic mechanism.
What are coagulation disorders?
Coagulation disorders include any disruption of the body’s ability to control blood clotting and are often characterized by excessive bleeding.
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?
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.
What is the coagulation cascade?
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).
What are the 2 clotting pathways?
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.
What is fibrinolysis?
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.
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?
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.
What is thromboembolic disease?
Thromboembolic disease is characterized by hypercoagulable states, which can manifest as deep vein thrombosis, pulmonary embolism, or coronary artery disease.
What conditions can result in intravascular clot formation?
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).
What are the 2 types of thrombi?
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.
Thromboembolic diseases can be treated using three different classes of antithrombotic agents. What are they?
- 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.
What is the aim of anticoagulant therapy?
The aim of anticoagulant therapy is to prevent the formation of intravascular thrombi, while minimizing the tendency to bleed.
What are the adverse effects of all anticoagulants?
All anticoagulants have bleeding as a major adverse effect.
- Anticoagulants do not alter the existing thrombi, but rather prevent further formation of thrombi.
What are the 2 main anticoagulant therapeutics commonly used to prevent or reduce coagulation of blood, thus prolonging the clotting time?
- Thrombin inhibitors
- Warfarin
What are the 3 main types of thrombin inhibitors?
1) Heparin and low molecular weight heparins
2) Oral Factor Xa Inhibitors
3) Direct Thrombin (Factor IIa) Inhibitors
What is heparin and how does it work?
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.
What are oral factor Xa inhibitors and how do they work? Provide an example
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.
What are direct thrombin (factor IIa) inhibitors and how do they work?
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.
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.
True
What is warfarin and how does it work?
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.
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?
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.
What are the disadvantages of warfarin?
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.
