By: David Manly and Stephan Moll, Chapel Hill, NC

Hello, and welcome to the January 2009 venous thrombosis update for the National Blood Clot Alliance (NBCA). This is David Manly from Chapel Hill, North Carolina. This update covers d-dimer testing, vitamin K supplementation and the “factor V Leiden paradox”.

To begin, a recent study in the Annals of Internal Medicine (ref. # 1) found that blood levels ofd-dimer predict who may develop a second venous blood clot once anticoagulation therapy has been stopped. For those who are not familiar with the term d-dimer, a d-dimer is a breakdown product from blood clots that can be measured in the blood. While there are a number of reasons why d-dimer levels can be elevated, high d-dimer levels can also indicate that a person’s clotting system is overly active: an overactive clotting system leads to clot formation, leads to clot breakdown, and leads to elevated d-dimers. This recent publication was a systematic review of all the published studies that had tested whether the D-dimer level (obtained with the patient off warfarin) predicts risk of recurrent clots. Seven good quality studies were found to be eligible. The composite data confirm that an elevated D-dimer predicts recurrence of clot: of patients with a negative D-dimer only 3.5 % had a second clot per year, whereas of patients with an elevated D-dimer, more than twice as many had a recurrence, i.e. 8.9 % per year. This review supports that d-dimer testing can be useful in determining a person’s risk of recurrent clots. A positive d-dimer may be one of the arguments to treat a patient with longer-term warfarin therapy, a negative d-dimer might argue for stopping warfarin.

The international normalized ratio, or INR, is a critical number for any patient monitoring oral anticoagulation therapy at home. The INR is based on a blood test called the prothrombin time (also referred to as “protime”) and the number it produces helps physicians adjust warfarin dosage. If the INR is too high an individual can be at risk for bleeding. If the INR is too low there is the risk for clotting. The therapeutic INR range for most patients on warfarin is 2-3. Warfarin anticoagulation needs to be closely monitored because it is susceptible to changes due to diet. Several clotting factors (i.e. proteins within the blood that help form blood clots) require vitamin K to be active and warfarin administration blocks this pathway. However, high levels of vitamin K through diet, such as green leafy vegetables like spinach, can greatly alter the INR thereby reducing the effectiveness of warfarin and making the body susceptible to clotting – meaning you are not being appropriately anticoagulated. A recent review publication (ref #2) summarizes three prospective and one retrospective study that studied Vitamin K supplementation in patients receiving warfarin. The summary of data shows that I some patients fluctuating INRs can, indeed, be stabilized, by taking a daily vitamin K tablet of 100 microgram, 150 microgram or 500 microgram. However, when starting such supplementation, patients need to be aware that (a) close INR monitoring in the first few days of starting such vitamin K supplementation is necessary, as warfarin doses may initially have to be increased, and (b) one should NOT abruptly stop taking the vitamin K tablets, as the INR could then suddenly increase significantly.

The “factor V Leiden paradox”: Factor V Leiden is a genetic clotting disorder afflicting one in twenty Caucasians and approximately 1 in 100 African-Americans in the United States. It has been long known that carriers of the factor V Leiden mutation have a clearly increased risk of deep vein thrombosis (i.e. blood clots in the leg veins), but that factor V Leiden is only a weak risk factor for blood clots in the lungs and pulmonary embolism. This differential effect of Factor V Leiden on the risk for these 2 types of vein clots is known as the “Factor V Leiden paradox”. To refresh our memory, a pulmonary embolism is a blood clot in the lungs that often results in immediate death. It has been estimated that 300,000 Americans die each year from pulmonary embolism, which is more than AIDs, breast cancer and traffic fatalities combined. A deep vein thrombosis is a clot in the deep veins, most often in the legs, which can break off and travel to the lung, causing a pulmonary embolism.

A recent study (ref #3) found that patients who have a deep vein thrombosis of the legs have a lower risk of also having a pulmonary embolism, if they have factor V Leiden, compared to patients who do not have the factor V Leiden mutation. Another recent study (ref #4) attempted to answer the factor V Leiden paradox, i.e. the increased risk of developing a deep vein thrombosis, but a lower risk for pulmonary embolism. The study looked at the location of blood clots, the number of veins affected with blood clots, time to actual diagnosis of the blood clot, differences in clot growth speed and blood clot structure. Unfortunately, no clear explanation for the factor V Leiden paradox was discovered. Thus, the only conclusion that can be drawn is that different clotting disorders lead to clots in different anatomic locations and with different risks of breaking off and traveling to the lung. Further research will focus on possible differences in clot growth speed or of clot structure to explain the “factor V Leiden paradox”.

Thank you for listening to the January 2009 update in venous thrombosis news and research presented by the National Blood Clot Alliance. We hope you join NBCA in the effort to raise awareness, educate and protect the American people against venous blood clots. And remember, patient advocacy and education is our top priority, so please inform us of any suggestions you may have to help make this podcast more educational. You can send your suggestions to That is spelled There is still much to do and NBCA greatly needs your support. Thank you.

Posted January 17, 2009

1. Verhovsek M et al. Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med. 2008 Oct 7;149:481-490.
2. Ford S et al. Vitamin K supplementation to decrease variability of International Normalized Ratio in patients on vitamin K antagonists: a literature review. Curr Opin Hematol. 2008 Sep;15(5):504-508.
3. Rossi E et al. The risk of symptomatic pulmonary embolism due to proximal deep venous thrombosis differs in patients with different types of inherited thrombophilia. Thromb Haemost 2008 (Oct);99:1030-1034.
4. van Stralen KJ et al. Mechanisms of the factor V Leiden paradox. Arterioscler Thromb Vasc Biol. 2008 Oct;28(10):1872-7. Epub 2008 Jul 10.

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