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Other Forms – Bleeding Disorders

by Paul Moss, PhD
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    00:01 patients with platelet functional abnormalities that will be suppressed. Now let us look at some of the clinical disorders that can lead to bleeding problems and I want to start with the vessel itself before we move on to consider the platelet and then the coagulation factors.

    00:15 Now let us look at the vessels vascular disorder. Now sometimes these can be inherited probably the most important one is represented with the clinical picture on the left.

    00:29 This is called hereditary hemorrhagic telangiectasia. It has an autosomal dominant inheritance and involves proteins which involved in collagen formation and strength. Endoglin is one of these molecules as often mutated and these telangiectasia developed in the skin, the mucous membranes you can see them on the tongue and also in internal organs. It can be a challenging condition to treat that we will use local factors sometimes and . . . perhaps even the hormonal treatment. There are several acquired disorders that can affect ability of vessels to stop blood clotting. Probably the most common is aging as our skin gets older, it gets thinner and you often see bruises in older people. Steroids as well thin in the skin and that is one reason you should not keep putting high dose steroids onto areas of skin. On the right is the hand of an elderly person, you can see some of that bruising on the skin, which become very thin. But two other conditions on that slide which are themselves have interest. One is a relatively rare condition, but very interesting, HenochSchonlein purpura.

    01:57 This is often see in young people after a recent infection and it is a vasculitis mediated through IgA and it leads to a purpura on the extensor part of the limbs and on the buttocks and finally the bottom a classic disease scurvy, which I am sure you know used to . . . many sailors who went around the world on long trips and did not get sufficient vitamin C.

    02:25 Vitamin C is quite important for maintaining collagen in its most active form and so bleeding was a major problem with scurvy. We rarely see it now, but sometimes if people on a very poor diet, you may see perifollicular hemorrhages in vitamin C deficiency.

    02:49 Now let us look at some platelet disorders and we will stop the disorders where they are low numbers of platelets so called thrombocytopenia and as you will see on the left, this can be due to increased destruction where the bottom decreased production. Let us look at some of the ways by which platelets can be destroyed. The most common is the immune disorder, immune mediated thrombocytopenia and here the body produces IgG antibodies against the platelets and that leads to their destruction. Sometimes it is triggered by the recent infection or sometimes it can occur out of the blue and it can be seen in young people or older people. They can be treated in a number of ways. Some of them are represented on the slide. Steroids we may remove the spleen perhaps or we can use drugs, which stimulate thrombopoietin-receptor activity. Other disorders, which reduced the platelet count, severe infections, there is a modest reduction in the platelet count during pregnancy, which is not clinically important and sometimes drugs can cause this effect. The cause that I will put up there thrombotic thrombocytopenic purpura, an important disorder I want to discuss it on the next slide.

    04:21 Platelets can also be reduced because of decreased production. The bone marrow simply not making enough platelets and we see that in patients who have bone marrow failure due to aplastic anemia or chemotherapy.

    04:35 If your platelet count is reduced, you tend to get bruising or mucous membrane bleeds and you will see on the right the patient with quite severe bruising and purpura on the skin due to thrombocytopenia. I will just talk a little bit more about that disorder that has a very long name thrombotic thrombocytopenic purpura. The name is quite interesting in itself because we are suggesting that it is low platelets here. It is from the cytopenic and you got purpura, bruising or thrombotic as well. So we are getting blood clots.

    05:13 So it is a paradox of clotting and bruising. How can this happen? Fortunately, it is a rare disorder, but it is fascinating pathophysiology. In this disorder, patients have a deficiency of the metalloprotease and enzyme. It is called ADAMTS13 as you can see on the slide.

    05:38 Sometimes it is congenital and we see this disorder in children. But in adults, it is autoimmune disorder and these patients have developed an antibody against that protein. One of the important functions of that protein is to break down von Willebrand factor into smaller components. It is VWF is made in very large aggregates and it needs to be broken down.

    06:06 If you are deficient in this enzyme, you have very large circulating multimers as we call them of VWF and they adhere the platelets very strongly to your vessels. That is why thrombocytopenic purpura because the platelets stick to the vessel. Those platelets plugs also damage red cells that are trying to get through and as you will see on the right that is a blood film NTTP and you will see all those damaged and sheared red cells and that produces them as you see hemolytic anemia and this can reduce blood flow to organs like the brain, the kidney and also cause of fever producing that classic spectrum of symptoms that I have put there. This can be a very serious disorder if it is not recognised with the high fatality rate and so it is important if it is treated and the best way to treat this with plasma exchange taking off the patient's plasma and infusing it from a donor.

    07:18 As well as the abnormalities in platelets number, we can also get disorders of platelet function.

    07:24 I have represented some here. They are all rare inherited disorders that we see in children and that is two of the classic types, Glanzmann's disorder and Bernard Souller disease and you can see that they are fat to the protein that we have learned about in this lecture, IIb/IIa and Ib and you now understand how that can lead to bleeding disorders. But at the bottom of course acquired disorders of platelet function, which is the most common of the use of antiplatelet drugs very widely used on millions of people around the world, aspirin, clopidogrel and so far. On the right, we have got a nice example of platelet aggregometry, platelet testing.

    08:14 Here we take blood platelets into a tube and we put light through that tube and if you put in various molecules such as ADP, collagen, adrenaline as you can see at the top, agonist that will cause the platelets to adhere and aggregate and more light can go through the system as you will see on the left, increasing light transmission and in green, you will see what happens when you add the agonist. The platelets adhere more light can shine through, but in the top in pink there are platelets from somebody with Glanzmann's disease, Glanzmann's thrombasthenia and you can see there is no platelet addition or aggregation at all. That is a commonly used test to assess platelet function.

    09:06 Now let us finish by talking about the coagulation disorders and will stop with the inherited types. Haemophilia A is the classic condition in this area, huge deficiency of factor VIII.

    09:20 It is X-linked and therefore only seen in boys with a frequency you can see around 30-100 per million. Now the gene may run in families passed on from the mother or it may result from a new mutation. So it sometimes spontaneously arises in the family. Now if this is untreated, it is a very serious disease. Tends to stop with bruising in babies, but throughout life you can get serious bleeds particularly in joints and muscles, very characteristic feature of this disease. You will see on the right what can happen to the joints after frequent bleeds into them and it can lead to a lot of disabling . . . Fortunately, factor VIII concentrates are now available. They can prevent this bleeding and also stop it once it is started. What we have seen in the treatment of haemophilia. It is a move away from waiting until patients have a bleed and then treating them to giving factor VIII prophylactically stop the bleeding and that is because if you look on the right on the top is a chart there showing that the amount of factor VIII in the blood determines the severity of the disease.

    10:49 You can see values that suggest severe, moderate or mild disease and with prophylactic therapy, only a modest increase, in fact, can dramatically reduce the number of bleeds of the patient gets and so that is the approach that we need to aspire to in the management of haemophilia.

    11:10 The bottom is haemophilia B, a rarest of type and that is due to deficiency factor IX.

    11:20 Other inherited disorders of coagulation are von Willebrand disease. This is due to a deficiency or inactivity of that factor VWF that we have mentioned so much during this talk and the prevalence of this is actually not that low 1 in 10,000 individuals and I put at the top right there reminder of the activity of the VWF linking the platelet through GPIb to the damaged cell on the collagen. VWF also carries factor VIII. That is one of its important functions. Now the bottom I have shown you electrophoresis diagram, which represents some of the subtypes of von Willebrand disease and you can see that there are several from type 1 whereas modest reduction of VWF to type III where there is really none at all.

    12:15 That is a very serious bleeding disorder. We can treat this disorder by local factors, drugs such as DDAVP, which release VWF and sometimes we need VWF infusions, which we can generate.Finally acquired disorders of the coagulation system and top here is disseminated intravascular coagulation. You will see on the right gangrene in the toes of this patient who has disseminated intravascular coagulation. Now this is a paradoxical disorder because in fact there is excessive coagulation. What that does is it depletes coagulation factors and leads the patient very prone to bleeding and it usually triggered by extreme events, severe infections perhaps severe problems in childbirth and the classic clinical feature of DIC is the patients bruise and bleed spontaneously. There may have blood taken a day or two ago and suddenly the venopuncture site starts to ooze. The whole-blood system fails to clot and that needs to be treated by infusion of things like fresh frozen plasma and platelets, perhaps fibrinogen through . . . A second disorder vitamin K deficiency.

    13:51 Sometimes it is seen in the newborn and those with liver disease. Vitamin K is needed to activate several clotting factors. Again that is why warfarin works as an antithrombotic agent by inhibiting vitamin K and finally a rare disorder acquired haemophilia.

    14:13 This is seen in adults and they have a clinical picture that resembles inherited haemophilia.

    14:18 This is developed not due to congenital deficiency, but due to an autoimmune disease against the factor VIII. They can be very challenging to treat.

    14:31 So In summary, haemostasis depends on the interaction of the blood vessel. the platelets and the coagulation system. Vessels and platelet disorders lead to bleeding into the skin and mucous membranes. Immune thrombocytopenia is the most common cause of thrombocytopenia.

    14:52 Haemophilia is the most important inherited coagulation disorder or can now be managed by the use of prophylactic factor VIII. I hope you have enjoyed this lecture on bleeding.


    About the Lecture

    The lecture Other Forms – Bleeding Disorders by Paul Moss, PhD is from the course Hematology: Advanced.


    Included Quiz Questions

    1. Disseminated intravascular coagulation
    2. Immune thrombocytopenic purpura
    3. Acquired haemophilia
    4. Neonatal thrombocytopenia
    5. Scurvy
    1. Hereditary haemorrhagic telangiectasia
    2. Haemophilia
    3. Warfarin overdose
    4. Immune thrombocytopenia
    5. Disseminated intravascular coagulation

    Author of lecture Other Forms – Bleeding Disorders

     Paul Moss, PhD

    Paul Moss, PhD


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