|Values are valid only on day of printing.|
Click CC to turn on closed captioning.
Published: May 2011Print Record of Viewing
Von Willebrand disease (VWD) is a commonly encountered inherited bleeding disorder that affects both males and females. It may also occur less frequently as an acquired disorder (acquired von Willebrand syndrome: AVWS). A published evidence-based guideline from the National Heart, Lung, and Blood Institute (NHLBI) expert panel outlines recommendations for the evaluation and management of VWD, including suggesting an approach for clinical and laboratory evaluation of individuals with bleeding symptoms, history of bleeding or conditions associated with increased bleeding risk.
This is the second in a four-part series on von Willebrand disease, and is also included in the series on test utilization.
Presenter: Dr. William L. Nichols
Welcome to Mayo Medical Laboratories' Hot Topics. These presentations provide short discussions of current topics and may be helpful to you in your practice.
Our presenter for this program is Robert D. McBane, MD, Consultant, Division of Cardiovascular Diseases and Mayo Special Coagulation Laboratories and Coagulation Clinical Centers, Professor of Medicine, Mayo Clinic College of Medicine at Mayo Clinic in Rochester, Minnesota. Dr. McBane will describe laboratory testing for thrombophilia and discuss current guidelines for anticoagulation therapy following deep vein thrombosis and pulmonary embolism.
Whenever we see somebody with an acute venous thromboembolism, the first thing that we ask is whether or not this individual has any acquired risk factors which would explain the thrombotic event. Here in this slide, you see not only independent risk factors for venous thromboembolism but you also can appreciate the associated odds ratio with each of the independent risk factors.
However, there are a number of individuals who present with an acute venous thrombotic event for whom an acquired risk factor cannot be identified. For these patients, we then go on to perform thrombophilia testing as outlined in this slide. A full thrombophilia assessment would include measures of antithrombin, protein C and protein S deficiencies in addition to genetic testing for factor V Leiden and the prothrombin gene mutation. Both lupus-like anticoagulant testing and antiphospholipid antibody assessment is also warranted.
These acquired and congenital risk factors help us because if you have a transient risk factor such as surgery, or major trauma, then the guidelines would suggest that you treat that individual for 3 months. However if one finds an aggressive thrombophilia, then indefinite warfarin therapy is recommended.
The definition of aggressive thrombophilia can be found in this slide and includes homozygous mutations or compound heterozygous mutations of factor V Leiden and the prothrombin gene mutation. Antiphospholipid antibody syndrome or deficiencies of either antithrombin, protein C or protein S also fall into this category.
Now let’s take a case of a patient who falls into neither of these categories. I would underscore that this particular patient represents a common individual or common clinical scenario presenting with a thrombotic disease. So this is a 37-year-old gentleman who complains of left-leg pain and swelling and is found by duplex ultrasound to have a popliteal deep vein thrombosis. He doesn’t have any antecedent risk factors to explain the thrombotic event. His family history is negative and he has undergone thrombophilia testing, all of which is negative or normal. He now comes to you 3 months after he has been on warfarin therapy and wants to know what to do next. And so in this slide is the potential advice that you might give to this patient.
When seeing patients with unprovoked or idiopathic venous thrombotic events and discerning the duration of therapy, most individuals will fall into 1 of 3 categories. Either they will want to stop warfarin therapy because they feel that they have had enough therapy and simply don’t want to continue with warfarin, or they will fall into the category where they don’t want to ever suffer another thrombotic event and would like to continue with warfarin therapy. But perhaps 50 percent of patients do not know what to do and it is for these individuals that this question applies.
So, I would argue that the correct answer for most patients such as this would be to do further testing.
When trying to ascertain how long to treat patients with idiopathic venous thrombotic events, the first thing I like to share with patients is the anticipated recurrence rate or natural history and what you can tell them what the ten year risk of recurrence will be. After an idiopathic thrombotic event, the 10-year risk of recurrence is about 30 percent as shown on this slide.
Well, do the treatment guidelines help us under these circumstances and the answer is they don’t really help us that much. Because for an idiopathic venous thrombotic event, the guidelines support the use of 3 months of anticoagulation. But they also support the use of prolonged secondary prophylaxis and both of these guidelines get a Grade 1A recommendation.
For these patients, we have taken to use the fibrin D-Dimer to help further risk stratify their risk of recurrence. And the way you do this study is that you have the patient take their prescribed duration of anticoagulants for treatment purposes, and then you stop the warfarin therapy for between 3 and 4 weeks and then you obtain a fibrin D-Dimer measure. If the fibrin D-Dimer is positive, they will have an associated risk of recurrent thrombosis of approximately10 percent per year. If, on the other hand, it is negative, then they will have between 2 and 3 percent risk of thrombosis per year if they remain off of Coumadin. This is essentially the same risk as major hemorrhage on Coumadin therapy which is perhaps between 2 and 3 percent. So if the risk of the disease is no better than the risk of treatment, then of course you would stop warfarin therapy.
So the use of fibrin D-Dimer has been assessed in a prospective trial called the PROLONG trial in this slide.
More than 600 patients with idiopathic venous thrombosis were treated for their thrombus for 3 months and then their warfarin was stopped. One month later, they had fibrin D-Dimer testing. If the D-Dimer was normal, then they were left off of warfarin therapy. If it was abnormal, then they were randomized to either to resume warfarin or to remain off of warfarin therapy.
This study, like the previous study I showed you, the risk of venous thrombosis if you had a positive D-Dimer and you were left off of warfarin therapy was approximately 10 percent per year.
The take home message then for idiopathic venous thrombosis is that if you are having trouble deciding whether or not to continue warfarin therapy after prescribed initial treatment, then you can stop warfarin and assess the D-Dimer 1 month later. If it is positive, then your patient has a risk of recurrence of about 10 percent per year; on the other hand, if it is negative, their risk of recurrence is about 3 percent per year and this is about the same risk as major hemorrhage on warfarin and this can help you nicely identify or risk stratify your patients with an idiopathic DVT.
Another tool that can be used for risk stratification is the presence or absence of residual vein thrombosis assessed by ultrasound and this is the study that was assessed in the DACUS trial. These investigators took 250 patients, treated them with warfarin for at least 3 months and then assessed residual thrombus by ultrasound. If there was residual thrombus, then they randomized patients either to resume warfarin or to stop warfarin; if there was no residual thrombus then they simply stopped warfarin therapy.
The way they defined residual thrombus was by compression ultrasonography. When they compressed the involved venous segment, if the diameter of the vein was more than 40 percent of the uncompressed venous diameter, this met criteria for residual venous thrombosis. On the other hand, if the thrombus by compression was less than 40 percent of the original vein diameter, then this was consistent with the definition of thrombus resolution.
In this study if you had no residual thrombus, the risk of recurrence was extremely low, and this is how this study was performed.
So this is how one would put this type of measure into practice. Here we have a duplex ultrasound of a patient who’s had a prior DVT and has been on warfarin therapy for 3 months. On the left you see the noncompressed images; on the right are the compressed images. What one does is to define the area of interest and to measure the diameters and compare the diameters and then this circumstance, you can see that the compressed images are less than 40 percent of the noncompressed and this would be consistent with thrombus resolution.
The take-home points then for idiopathic deep vein thrombosis are that the risk of recurrence is relatively high. The risk of major bleeding while on warfarin therapy is approximately 2 percent per year when warfarin is well managed. And the risk stratification tools are available including fibrin D-Dimer and a duplex ultrasound for residual vein thrombosis.
But now let’s take our original patient and assume that instead of having a popliteal venous thrombosis, he has bilateral pulmonary emboli. After 3 months of warfarin therapy, what would your recommendations be? These recommendation options are the same as I have outlined with my initial questions.
For this individual I would consider prolonged warfarin therapy because of the risks associated with recurrence.
First of all, note the difference in mortality risk comparing pulmonary embolism to deep vein thrombosis. Approximately one-third of patients with a pulmonary embolism will die suddenly and the 30-day mortality is high at 45 percent.
Furthermore, the incident type of venous thrombosis helps to predict the type of recurrent venous thrombosis if recurrence should occur. For example, in this slide, if the incident event was a deep vein thrombosis and the individual suffers a recurrent thrombus, it is more likely to be another deep vein thrombosis in the leg as compared to a pulmonary embolism.
However, if the incident event was a pulmonary embolism and the patient has a recurrent venous thrombosis, it is much more likely to be another pulmonary embolism compared to a deep vein thrombosis.
Moreover, one of the strongest independent predictors of death within 7 days of a venous thrombus is recurrent pulmonary embolism.
So the take-home point for idiopathic pulmonary embolism is that recurrent event is most likely to another pulmonary embolism. Furthermore, pulmonary embolism carries a high mortality risk which is considerably higher than deep vein thrombosis. Therefore, in selective patients with low risk of bleeding and good anticoagulation monitoring, prolonged secondary prophylaxis should be considered with warfarin therapy. Thank you very much for your time and attention.
Thank you, Dr. McBane, for your presentation. The content discussed in this Hot Topic is an example of what will be covered during the upcoming conference, Clinical and Laboratory Update in Thrombosis and Anticoagulation, which will be held August 4-5, 2011, in Rochester, Minnesota. This conference will include information on the advances in the evaluation and management of common thrombotic disorders as well as specific aspects of uncommon thrombotic diseases. Lectures and case studies will be presented by Mayo Clinic faculty with an opportunity throughout both days to ask questions and discuss difficult diagnostic and management issues. For additional information, visit the conference web site.
Thank you! Questions or requests can be emailed to the address shown.