Thrombosis – Thrombosis and Anti-Thrombotic Therapy

by Paul Moss, PhD

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    00:02 Hello, Welcome to this lecture on thrombosis and antithrombotic therapy. We will see in this lecture thrombosis is one of the most important problems in medicine at the current time.

    00:16 Some people carry an inherited predisposition to venous thrombosis and environmental risk factors include bed rest or surgery. Arterial thrombosis is primarily the result of atherosclerosis and heparin and warfarin have been mainstays of anti-thrombotic therapy, but a range of new oral agents are now available. Let us introduce thrombosis. Thrombi are plugs consisting primarily of platelets and fibrin and, of course, the main clinical problem that arises from this is ischemia, lack of blood supply that happens beyond the clot.

    01:03 Now thrombi may occur in either the arterial or the venous circulation and an important is thrombophilia that refers to the inherited predisposition to thrombosis. On the right, you will see a very large thrombus in the pulmonary veins.

    01:23 Let us start by discussing arterial thrombosis. These arise on areas of atherosclerosis particularly when there is plaque rupture. When the plaques formed enough respiratory break and platelet adhere to that site. A platelet adhesion, aggregation and release may actually serve to promote the development of atherosclerotic lesions and that might be one reason why aspirin is so effective in reducing the risk of atherosclerotic events. But as well as ischemia, thrombosis may also lead to the release of emboli, the flow to downstream vessels sometimes seen from atherosclerotic plaques in the neck leading to emboli into the brain.

    02:20 Atherosclerosis is being one of the major problems in human health over the last few decades and we know a lots about the risk factors cholesterol, hypertension and smoking. There is some good news here because the incidence and also the mortality from atherosclerotic disorders has increased markedly in recent years as we served to reduce those risk factors and control them.

    02:49 Venous thrombosis has three classic risk factors used to be known as Virchow's triad.

    02:57 One is when the blood slows down. Secondly the blood may be hypercoagulable sometimes see perhaps in pregnancy after surgery or trauma and finally when the vessel wall is damaged, which can trigger adhesion of platelets to that damage and you can see those three factors often occur in patients in hospital beds after surgery. Let us discuss inherited thrombophilia because it has been shown that after 30 percent of people who develop a venous thrombosis do have a genetic predisposition of thrombosis. Now to understand these disorders, we need to discuss the natural physiological activity of something called protein C. Look at that diagram on the right. On the top left, we can see thrombin. Thrombin is a key molecule in the coagulation cascade and it activates fibrinogen to release the fibrin, but as well as promoting coagulation at also leads to inactivation of coagulation factors through a negative feedback pathway and the mechanism is represented there. It happens by a fascinating route. Thrombin binds together molecule on the surface of the endothelium called thrombomodulin.

    04:32 Once it is found, it can then activate protein C, which can see in red. Now protein C needs protein S as a cofactor, but those two together can then inactivate the active forms of factor V and factor VIII, which are critical cofactors for coagulation. So you can see the C and S very important in limiting the amount of active coagulation factors . . . of thrombosis.

    05:09 An important inherited thrombophilia is factor V Leiden, which we can now start to understand.

    05:18 This is an inherited allele in the factor V genes very common in many populations after 3 percent of the population perhaps it has been selected in evolution because it does provide a little bit more protection against bleeding problems. But this allele at factor V makes factor V slightly more difficult to cleave by the activated protein C.

    05:48 Heterozygotes have a 5-8 fold risk of thrombophilia from this disorder whereas homozygotes have a huge 30-140 fold risk of thrombosis if they have a factor V Leiden from both the mother and the father. Protein C or S can be also deficient. These are rare disorders and usually seen an autosomal recessive inheritance from the mother or the father. Sometimes babies are born with protein C or S deficiency from both mother and the father. That is a very devastating disorder, which leads to very severe thrombosis in early life. Antithrombin can also deficient and that is another thing, which can be checked in tests of thrombophilia.

    06:45 Now let us look at some of the risk factors in life that can put a risk of developing thrombus. This can be seen in a range of states. Some are listed there on the left. Postoperatively because of rest or increased coagulability of the blood or indeed vessel damage, immobility.

    07:08 Many malignant disorders trigger excess blood coagulation. Oestrogen therapy and the use of the contraceptive pill can increase the risk of thrombosis. Ageing is a very important risk factor and that is actually shown on the right where you can see new episodes of venous thromboembolism plotted in terms of incidence on the Y-axis against age on the X-axis and you can see that very steep increase after the age of 60. Antiphospholipid syndrome and myeloproliferative disorders also lead to an increased risk of thrombophilia.

    07:53 How do we make the diagnosis of a thrombosis? Well, to investigate thrombophilia we can look at the blood count to check the platelets, we can do clotting tests and we can also do genetic tests to look for the presence of factor V abnormalities in protein C or protein S. A deep vein thrombosis is usually diagnosed by the clinical picture very commonly in the lower leg. The calf may be swollen and warm and may be tendouness but that is noy at a very reliable picture and we will need other tests before we could commit a patient to anti thrombotic therapy. D-dimers or fragments are released after blood clotting and they are raised in patients with deep vein thrombosis and imaging in the form of an ultrasound or perhaps MRI scan is also needed.

    About the Lecture

    The lecture Thrombosis – Thrombosis and Anti-Thrombotic Therapy by Paul Moss, PhD is from the course Hematologic Disorders.

    Included Quiz Questions

    1. Swelling, tenderness and warmth in the lower leg
    2. Angina
    3. Decreased D-dimer concentrations in blood
    4. Sudden onset of cold and blue toes
    5. Purpura on the limbs
    1. Slowing down and stagnation of blood
    2. Cholesterol
    3. Hypertension
    4. Smoking
    5. Arteriosclerosis
    1. Factor V Leiden
    2. Protein C deficiency
    3. Protein S deficiency
    4. Antithrombin III deficiency
    5. Hemophilia
    1. Protein C is unable to cleave activated Factor V
    2. Factor V is unable to cleave activated protein C
    3. Protein C is unable to cleave activated protein S
    4. Factor V is unable to cleave activated protein S
    5. Factor V is unable to cleave activated antithrombin II
    1. X-ray
    2. Clinical picture
    3. MRI
    4. Ultrasound
    5. Elevated D-dimer

    Author of lecture Thrombosis – Thrombosis and Anti-Thrombotic Therapy

     Paul Moss, PhD

    Paul Moss, PhD

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