This 6/30/2012 question from a physician arrived through the American Society for Clinical Laboratory Science Consumer Web Forum. “Does delayed fibrinolysis in a known factor V Leiden (FVL) mutation patient reduce the value of a negative D-dimer test?”
George’s initial response: Thank you for your question. I was prepared to answer that there is no connection, but some recent references indeed link FVL with fibrinolysis. The most interesting is lmas E, Suvajac N, Jilma B, Weiler H, Borggrefe M, Dempfle CE. Factor V Leiden mutation enhances fibrin formation and dissolution in vivo in a human endotoxemia model. Blood 2010;116:801–5. Surprisingly, they found FVL actually mitigates the incidence and severity of disseminated intravascular coagulation (DIC). Quoting the conclusion in their abstract, “Patients with FVL displayed a more sustained increase in plasmin-plasmin inhibitor complex after 4, 6, and 24 hours. Patients with FVL mutation also displayed higher levels of D-dimer and fibrinogen-fibrin degradation products in plasma after 24 hours. Patients with FVL generate higher levels of soluble fibrin, which may serve as cofactor in tissue plasminogen activator-induced plasminogen activation, leading to a more sustained activation of fibrinolysis with production of more fibrinogen- and fibrin-degradation products.” Given that they recorded higher levels of D-dimer in FVL than in wild-type, I would conclude that a negative D-dimer in a FVL patient remains effective in ruling out a thrombotic event.
Several additional references suggest that factor XIII activation, controlled by endothelial cell thrombomodulin, is less well controlled in FVL patients. Thus XIII activation is more rapid, leading to earlier clot cross-linking. However, none of these references measure D-dimer, leaving the question open to speculation.
This intriguing follow-up arrived July 3: “I have more than a professional interest in FVL, as I am a 70 year old FVL heterozygous patient with a past history of 3 major DVTs and 1 PE 28 years ago. I have been on Coumadin for 28 years. Two recent episodes of potential DVTs were ruled out with negative D-dimer quantitative tests. However I now absolutely have a moderate superficial lower leg thrombophlebitis, and 2 negative D-dimer tests performed on day 2 and 6, with another planned for day 11. I realize that both my age (old), and my Coumadin use may reduce the value of the D-dimer test. FVL persons have an exaggerated risk of DVT and PE. Therefore we make up a larger percentage of persons who may need and receive D-dimer testing than the percentage of FVL in the population. Thank you for continuing your search for the answer to my question.
Doctor, year by year I find myself less inclined to use terms like “old,” or “geriatric.” Nevertheless, using “elderly,” I’ve found a number of primary research article publications on D-dimer in people over 70, represented by: Tardy B, Tardy-Poncet B, Viallon A, Lafond P, Page Y, Venet C, Bertrand JC. Evaluation of D-dimer ELISA test in elderly patients with suspected pulmonary embolism. Thromb Haemost 1998 79: 38–41. Their conclusion was, “In a geriatric population, conventional ELISA D-dimer is a good marker to exclude PE but, due to the co-morbid conditions, only a few patients presented with D-dimer values less than 500 ng/mL.”
Based on this and my general knowledge of D-dimer, your situation stumps me. Indeed, as we age we accumulate more and more low-grade chronic inflammatory conditions like arthritis or sinusitis that raise our D-dimer regardless of thrombotic events. This is the basis for saying that D-dimer’s clinical efficacy is reduced as we age, not that we produce less D-dimer. Further, the D-dimer assay works in people taking Coumadin, indeed, some clinicians like to run a D-dimer before discontinuing Coumadin as a predictor of a new thrombotic event. My only question, and one that you have perhaps already answered with the phrase, “D-dimer quantitative’” is whether your laboratory is using a sensitive quantitative D-dimer or one of the less sensitive quick turn-around semiquantitative assays. The latter can sometimes generate false negatives. I apologize for an equivocal answer, but have “farmed” this post to a few colleagues who are D-dimer experts and who may see the answer at a glance. Geo.
I am coming into this debate rather late but i would like to
I am coming into this debate rather late but i would like to comment on the use of d-dimer
1. The use of d-dimer assays to exclude VTE is well established with clinical management trials, although this is not the case with all d-dimer assays since many d-dimer manufacturers seem to rely on their comparisons with the “gold standard” Vidas assay. The 2011 CLSI guidelines “Quantitative D-Dimer for the Exclusion of Venous Thromboembolic Disease; Approved Guideline H59-A are helpful in determining whether your d-dimer assay can be used for ‘exclusion of VTE” together with a clinical risk score or is an “aid to diagnosis of VTE”
2. There is no where near the same amount of data and clinical studies for d-dimer to be used for other indications eg rule out rethrombosis, superficial thrombosis etc because the appropriate cutoffs have not been established.