D-dimer

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D-dimer (or D dimer) is a fibrin degradation product (or FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is so named because it contains two crosslinked D fragments of the fibrin protein.[1]

D-dimer concentration may be determined by a blood test to help diagnose thrombosis. Since its introduction in the 1990s, it has become an important test performed in patients with suspected thrombotic disorders. While a negative result practically rules out thrombosis, a positive result can indicate thrombosis but does not rule out other potential causes. Its main use, therefore, is to exclude thromboembolic disease where the probability is low. In addition, it is used in the diagnosis of the blood disorder disseminated intravascular coagulation.[1]

Principles[edit]

Principles of D-dimer testing

Coagulation, the formation of a blood clot or thrombus, occurs when the proteins of the coagulation cascade are activated, either by contact with damaged blood vessel wall (intrinsic pathway) or by activation of factor VII by tissue activating factors. Both pathways lead to the generation of thrombin, an enzyme that turns the soluble blood protein fibrinogen into fibrin, which aggregates into proteofibrils. Another thrombin-generated enzyme, factor XIII, then crosslinks the fibrin proteofibrils at the D fragment site, leading to the formation of an insoluble gel which serves as a scaffold for blood clot formation.[1]

The circulating enzyme plasmin, the main enzyme of fibrinolysis, cleaves the fibrin gel in a number of places. The resultant fragments, "high molecular weight polymers", are digested several times more by plasmin to lead to intermediate and then to small polymers (fibrin degradation products or FDPs). The cross-link between two D fragments remains intact, however, and these are exposed on the surface when the fibrin fragments are sufficiently digested. The typical D-dimer containing fragment contains two D domains and one E domain of the original fibrinogen molecule.[1]

D-dimers are not normally present in human blood plasma, except when the coagulation system has been activated, for instance because of the presence of thrombosis or disseminated intravascular coagulation. The D-dimer assay depends on the binding of a monoclonal antibody to a particular epitope on the D-dimer fragment. Several detection kits are commercially available; all of them rely on a different monoclonal antibody against D-dimer. For some of these, the area of the D-dimer to which the antibody binds is known. The binding of the antibody is then measured quantitatively by one of various laboratory methods.[1]

Indications[edit]

D-dimer testing is of clinical use when there is a suspicion of deep venous thrombosis (DVT), pulmonary embolism (PE) or disseminated intravascular coagulation (DIC).[2] It is under investigation in the diagnosis of aortic dissection.[3][4]

For DVT and PE, there are possible various scoring systems that are used to determine the a priori clinical probability of these diseases; the best-known were introduced by Wells et al. (2003).

  • For a very high score, or pretest probability, a D-dimer will make little difference and anticoagulant therapy will be initiated regardless of test results, and additional testing for DVT or pulmonary embolism may be performed.
  • For a moderate or low score, or pretest probability:[5]
    • A negative D-dimer test will virtually rule out thromboembolism: the degree to which the D-dimer reduces the probability of thrombotic disease is dependent on the test properties of the specific test used in the clinical setting: most available D-dimer tests with a negative result will reduce the probability of thromboembolic disease to less than 1% if the pretest probability is less than 15-20%
    • If the D-dimer reads high, then further testing (ultrasound of the leg veins or lung scintigraphy or CT scanning) is required to confirm the presence of thrombus. Anticoagulant therapy may be started at this point or withheld until further tests confirm the diagnosis, depending on the clinical situation.

In some hospitals, they are measured by laboratories after a form is completed showing the probability score and only if the probability score is low or intermediate. This reduces the need for unnecessary tests in those who are high-probability.[6] Performing the D-dimer test first can avoid a significant proportion of imaging tests and is less invasive. Since the D-dimer can exclude the need for imaging, specialty professional organizations recommend that physicians use D-dimer testing as an initial diagnostic.[7][8][9][10]

Test properties[edit]

Various kits have a 93-95% sensitivity (true positive rate) and about 50% specificity (true negative rate) in the diagnosis of thrombotic disease.[11]

  • False positive readings can be due to various causes: liver disease, high rheumatoid factor, inflammation, malignancy, trauma, pregnancy, recent surgery as well as advanced age.[12]
  • False negative readings can occur if the sample is taken either too early after thrombus formation or if testing is delayed for several days. Additionally, the presence of anti-coagulation can render the test negative because it prevents thrombus extension.
  • False values may be obtained if the specimen collection tube is not sufficiently filled (false low value if underfilled and false high value if overfilled). This is due to the dilutional effect of the anticoagulant (the blood must be collected in a 9:1 blood to anticoagulant ratio).
  • Likelihood ratios are derived from sensitivity and specificity to adjust pretest probability.

In interpretation of the d-dimer, for patients over age 50 a value of ageX10 may be abnormal.[13][14]

History[edit]

D-dimer was originally described in the 1970s, and found its diagnostic application in the 1990s.[1]

References[edit]

  1. ^ a b c d e f Adam SS, Key NS, Greenberg CS (March 2009). "D-dimer antigen: current concepts and future prospects". Blood 113 (13): 2878–2887. doi:10.1182/blood-2008-06-165845. PMID 19008457. 
  2. ^ General Practice Notebook > D-dimer Retrieved September 2011
  3. ^ Suzuki, T.; Distante, A.; Eagle, K. (2010). "Biomarker-assisted diagnosis of acute aortic dissection: How far we have come and what to expect". Current Opinion in Cardiology 25 (6): 541–545. doi:10.1097/HCO.0b013e32833e6e13. PMID 20717014.  edit
  4. ^ Ranasinghe, A. M.; Bonser, R. S. (2010). "Biomarkers in Acute Aortic Dissection and Other Aortic Syndromes". Journal of the American College of Cardiology 56 (19): 1535–1541. doi:10.1016/j.jacc.2010.01.076. PMID 21029872.  edit
  5. ^ Wells PS, Anderson DR, Rodger M et al. (2003). "Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis". N. Engl. J. Med. 349 (13): 1227–1235. doi:10.1056/NEJMoa023153. PMID 14507948. 
  6. ^ Rathbun, SW; TL Whitsett; SK Vesely; GE Raskob (2004). "Clinical utility of D-dimer in patients with suspected pulmonary embolism and nondiagnostic lung scans or negative CT findings". Chest 125 (3): 851–855. doi:10.1378/chest.125.3.851. PMC 1215466. PMID 15006941. 
  7. ^ American College of Physicians, "Five Things Physicians and Patients Should Question", presented by ABIM Foundation, Choosing Wisely (American College of Physicians), retrieved August 14, 2012 
  8. ^ Fesmire, F. M.; Brown, M. D.; Espinosa, J. A.; Shih, R. D.; Silvers, S. M.; Wolf, S. J.; Decker, W. W.; American College of Emergency Physicians (2011). "Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department with Suspected Pulmonary Embolism". Annals of Emergency Medicine 57 (6): 628–652.e75. doi:10.1016/j.annemergmed.2011.01.020. PMID 21621092.  edit
  9. ^ Torbicki, A.; Perrier, A.; Konstantinides, S.; Agnelli, G.; Galiè, N.; Pruszczyk, P.; Bengel, F.; Brady, A. J. B.; Ferreira, D.; Janssens, U.; Klepetko, W.; Mayer, E.; Remy-Jardin, M.; Bassand, J. -P.; Vahanian, A.; Camm, J.; De Caterina, R.; Dean, V.; Dickstein, K.; Filippatos, G.; Funck-Brentano, C.; Hellemans, I.; Kristensen, S. D.; McGregor, K.; Sechtem, U.; Silber, S.; Tendera, M.; Widimsky, P.; Zamorano, J. L.; Zamorano, J. -L. (2008). "Guidelines on the diagnosis and management of acute pulmonary embolism: The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)". European Heart Journal 29 (18): 2276–2315. doi:10.1093/eurheartj/ehn310. PMID 18757870.  edit
  10. ^ Qaseem, A.; Snow, V.; Barry, P.; Hornbake, E. R.; Rodnick, J. E.; Tobolic, T.; Ireland, B.; Segal, J.; Bass, E.; Weiss, K. B.; Green, L.; Owens, D. K. (2007). "Current Diagnosis of Venous Thromboembolism in Primary Care: A Clinical Practice Guideline from the American Academy of Family Physicians and the American College of Physicians". The Annals of Family Medicine 5: 57. doi:10.1370/afm.667.  edit
  11. ^ Schrecengost JE, LeGallo RD, Boyd JC et al. (September 2003). "Comparison of diagnostic accuracies in outpatients and hospitalized patients of D-dimer testing for the evaluation of suspected pulmonary embolism". Clinical Chemistry 49 (9): 1483–1490. doi:10.1373/49.9.1483. PMID 12928229. 
  12. ^ Kabrhel, Christopher; Mark Courtney, D.; Camargo, Carlos A.; Plewa, Michael C.; Nordenholz, Kristen E.; Moore, Christopher L.; Richman, Peter B.; Smithline, Howard A.; Beam, Daren M.; Kline, Jeffrey A. (14 May 2010). "Factors Associated With Positive D-dimer Results in Patients Evaluated for Pulmonary Embolism". Academic Emergency Medicine 17 (6): 589–597. doi:10.1111/j.1553-2712.2010.00765.x. PMC 3538031. PMID 20624138. Retrieved 17 January 2014. 
  13. ^ van Es J, Mos I, Douma R, Erkens P, Durian M, Nizet T et al. (2012). "The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded.". Thromb Haemost 107 (1): 167–71. doi:10.1160/TH11-08-0587. PMID 22072293. 
  14. ^ Douma RA, le Gal G, Söhne M, Righini M, Kamphuisen PW, Perrier A et al. (2010). "Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts.". BMJ 340: c1475. doi:10.1136/bmj.c1475. PMC 2847688. PMID 20354012. 

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