How the Blood Clots?
Bateeilee blogs admin will post How the Blood Clots?. The clotting mechanism is one of the most important and complex of
physiologic systems. Blood must flow freely through the blood vessels
in order to sustain life. But if a blood vessel is traumatized, the
blood must clot to prevent life from flowing away. Thus, the blood must
provide a system that can be activated instantaneously – and that can
be contained locally – to stop the flow of blood. This system is called
the clotting mechanism.
To treat or prevent abnormal blood clotting, doctors must understand the multifaceted aspects of the clotting mechanism. The following explanation is greatly simplified, but is designed to provide a basic understanding of how the many drugs used to treat clotting problems work, and some basis for assessing the treatments your doctor may prescribe for you.
The thrombin system consists of several blood proteins that, when bleeding occurs, become activated. The activated clotting proteins engage in a cascade of chemical reactions that finally produce a substance called fibrin. Fibrin can be thought of as a long, sticky string. Fibrin strands stick to the exposed vessel wall, clumping together and forming a web-like complex of strands. Red blood cells become caught up in the web, and a “red clot” forms.
A mature blood clot consists of both platelets and fibrin strands. The strands of fibrin bind the platelets together, and “tighten” the clot to make it stable.
In arteries, the primary clotting mechanism depends on platelets. In veins, the primary clotting mechanism depends on the thrombin system. But in reality, both platelets and thrombin are involved, to one degree or another, in all blood clotting.
Figure 2. The atherosclerotic plaque has developed an ulcer ("U").
Figure 3. The platelets have been activated (i.e., made "sticky") by their exposure to the ulcerated plaque. They begin to aggregate (to stick) to the surface of the ulcer.
Figure 4. The thrombin system has been activated (also by exposure of the blood to the surface of the ulcer), and fibrin strands begin to form, connecting the aggregated platelets, and drawing them together.
Figure 5. A mature clot is now present, superimposed on the atherosclerotic plaque. This clot makes the partial obstruction of the coronary artery substantially worse. The arrow indicates the increased sluggishness and turbulence of blood flow through the artery. This patient most likely now has unstable angina, and if blood flow is sluggish enough, some of the heart cells supplied by this artery may die.
If the artery becomes totally occluded by a clot, a classic heart attack (myocardial infarction) will occur.
Low molecular weight heparin: enoxaparin, dalteparin. LMWH is a “purified” derivative of heparin. Its major advantages are that it can be given as a skin injection (which almost anyone can learn to do in a few minutes), and does not need to be closely monitored with blood tests. Thus, unlike heparin, LMWH can be administered safely on an outpatient basis.
Coumadin. Coumadin is an oral anti-thrombin drug that can be taken chronically. The dose must be carefully monitored by following the prothrombin time (PT), a blood test.
Drugs that “dissolve” fibrin – the fibrinolytic drugs. These powerful drugs actually dissolve fibrin strands that have already formed.
TPA, streptokinase, urokinase. These are the intravenous drugs that are administered acutely during the first few hours of an acute heart attack or stroke, to attempt to re-open an occluded artery, and prevent permanent tissue damage.
Ticlopidine (Ticlid) and clopidrogel (Plavix). These drugs are somewhat more powerful than the first group, but can be poorly tolerated and can have important side effects. They are generally used in patients who need, but cannot tolerate, aspirin.
IIb/IIIa inhibitors: abciximab (Reopro), eptifabitide (Integrilin), tirofiban (Aggrastat). The IIb/IIIa inhibitors are the most powerful group of platelet inhibitors. They inhibit a receptor on the surface of platelets (the so-called IIb/IIIa receptor) that is essential for platelet stickiness. Their chief usage is to prevent acute clotting after interventional procedures (such as angioplasty and stent placement), and in patients with acute coronary artery syndromes, such as unstable angina. These drugs are very expensive and (in general) must be given intravenously.
To treat or prevent abnormal blood clotting, doctors must understand the multifaceted aspects of the clotting mechanism. The following explanation is greatly simplified, but is designed to provide a basic understanding of how the many drugs used to treat clotting problems work, and some basis for assessing the treatments your doctor may prescribe for you.
How does the blood clot?
There are two major facets of the clotting mechanism – the platelets, and the thrombin system. The platelets are tiny cellular elements, made in the bone marrow, that travel in the bloodstream waiting for a bleeding problem to develop. When bleeding occurs, chemical reactions change the surface of the platelet to make it “sticky.” Sticky platelets are said to have become “activated.” These activated platelets begin adhering to the wall of the blood vessel at the site of bleeding, and within a few minutes they form what is called a “white clot.” (A clump of platelets appears white to the naked eye.)
The thrombin system consists of several blood proteins that, when bleeding occurs, become activated. The activated clotting proteins engage in a cascade of chemical reactions that finally produce a substance called fibrin. Fibrin can be thought of as a long, sticky string. Fibrin strands stick to the exposed vessel wall, clumping together and forming a web-like complex of strands. Red blood cells become caught up in the web, and a “red clot” forms.
A mature blood clot consists of both platelets and fibrin strands. The strands of fibrin bind the platelets together, and “tighten” the clot to make it stable.
In arteries, the primary clotting mechanism depends on platelets. In veins, the primary clotting mechanism depends on the thrombin system. But in reality, both platelets and thrombin are involved, to one degree or another, in all blood clotting.
How the Blood Clots - using a coronary artery as an example.
Figure 1. A coronary artery is shown that has an atherosclerotic plaque ("AP") partially occluding the lumen (opening) of the artery. Platelets within the blood are shown ("P"). The flow of blood through the artery is indicated by the long arrow. The patient with this artery likely has stable angina.
Figure 2. The atherosclerotic plaque has developed an ulcer ("U").
Figure 3. The platelets have been activated (i.e., made "sticky") by their exposure to the ulcerated plaque. They begin to aggregate (to stick) to the surface of the ulcer.
Figure 4. The thrombin system has been activated (also by exposure of the blood to the surface of the ulcer), and fibrin strands begin to form, connecting the aggregated platelets, and drawing them together.
Figure 5. A mature clot is now present, superimposed on the atherosclerotic plaque. This clot makes the partial obstruction of the coronary artery substantially worse. The arrow indicates the increased sluggishness and turbulence of blood flow through the artery. This patient most likely now has unstable angina, and if blood flow is sluggish enough, some of the heart cells supplied by this artery may die.
If the artery becomes totally occluded by a clot, a classic heart attack (myocardial infarction) will occur.
How can the clotting mechanism produce problems?
The clotting system, like all complex physiologic systems, can produce problems. Blood clots forming on atherosclerotic plaques in the arteries are the major cause of heart attack and stroke. Blood clots forming in the veins of the legs produce a painful condition called phlebitis, and when these venous blood clots break off (“embolize”) they move into the lungs and produce a dangerous condition called pulmonary embolus.
How can abnormal blood clotting be treated?
Drugs used for preventing or treating abnormal blood clotting can be aimed either at the platelets, or at the thrombin system. While they all have their own profile of side effects, one side effect common to all these drugs is excess bleeding. They must all be used with appropriate precautions.
Drugs aimed at the thrombin system.
Drugs that prevent further fibrin from forming. These drugs, which inhibit one or more of the proteins involved in the thrombin clotting system, are used for both arterial and venous clotting problems. Heparin. Heparin is an intravenous drug that has an immediate (within seconds) inhibitory effect on the thrombin system. Its dosage can be adjusted frequently, following the PTT blood test (the partial thromboplastin time) to achieve the desired effect.
Low molecular weight heparin: enoxaparin, dalteparin. LMWH is a “purified” derivative of heparin. Its major advantages are that it can be given as a skin injection (which almost anyone can learn to do in a few minutes), and does not need to be closely monitored with blood tests. Thus, unlike heparin, LMWH can be administered safely on an outpatient basis.
Coumadin. Coumadin is an oral anti-thrombin drug that can be taken chronically. The dose must be carefully monitored by following the prothrombin time (PT), a blood test.
Drugs that “dissolve” fibrin – the fibrinolytic drugs. These powerful drugs actually dissolve fibrin strands that have already formed.
TPA, streptokinase, urokinase. These are the intravenous drugs that are administered acutely during the first few hours of an acute heart attack or stroke, to attempt to re-open an occluded artery, and prevent permanent tissue damage.
Drugs aimed at platelets.
These three groups of drugs, in one way or another, reduce the “stickiness” of platelets. They are used most commonly in preventing arterial clots from forming. Aspirin and diypyramidole. These drugs have a modest effect on platelet “stickiness,” but have few important side effects.
Ticlopidine (Ticlid) and clopidrogel (Plavix). These drugs are somewhat more powerful than the first group, but can be poorly tolerated and can have important side effects. They are generally used in patients who need, but cannot tolerate, aspirin.
IIb/IIIa inhibitors: abciximab (Reopro), eptifabitide (Integrilin), tirofiban (Aggrastat). The IIb/IIIa inhibitors are the most powerful group of platelet inhibitors. They inhibit a receptor on the surface of platelets (the so-called IIb/IIIa receptor) that is essential for platelet stickiness. Their chief usage is to prevent acute clotting after interventional procedures (such as angioplasty and stent placement), and in patients with acute coronary artery syndromes, such as unstable angina. These drugs are very expensive and (in general) must be given intravenously.
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